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One hundred years of allergen immunotherapy: Time to ring the changes

      One hundred years have passed since Noon
      • Noon L.
      Prophylactic inoculation against hayfever.
      made his original observation that prophylactic inoculation with grass pollen extract in patients with hay fever resulted in effective desensitization, as shown by a decrease in immediate conjunctival sensitivity to grass pollen. Interestingly, in this centenary year of immunotherapy, despite many advances, we continue to use whole allergen extracts administered through the subcutaneous route as usual practice.
      The observation by Prausnitz and Küstner
      • Prausnitz C.
      • Küstner H.
      Studien über die Ueberempfindlichkeit.
      that a serum factor (“reagin”) could transfer immediate allergen sensitivity as shown by means of skin testing was followed by the observation by Cooke et al
      • Cooke R.A.
      • Barnard J.H.
      • Hebald S.
      • Stull A.
      Serological immunity with co-existing sensitisation in a type of human allergy (hay fever).
      that serum obtained after pollen immunotherapy could confer “immunity as well as hypersensitivity” (Table I). These seminal observations long preceded the discovery of IgE antibody as “reagin” by Ishizaka et al
      • Ishizaka K.
      • Ishizaka T.
      • Hornbrook M.M.
      Physiochemical properties of reaginic antibody V. Correlation of reaginic activity with yEglobulin antibody.
      and Johansson and Bennich

      Johansson SGO, Bennich H. Studies on a new class of human immunoglobulins. 1. Immunological properties. Nobel symposium 3, gamma globulins, structure and control of biosynthesis. P193. (Stockholm, June 12-17, 1967.) Almqvist and Wiksell.

      and the concept of allergen-specific IgG “blocking antibodies”
      • Gleich G.J.
      • Zimmermann E.M.
      • Henderson L.L.
      • Yunginger J.W.
      Effect of immunotherapy on immunoglobulin E and immunoglobulin G antibodies to ragweed antigens: a six-year prospective study.
      with functional activity
      • Shamji M.H.
      • Wilcock L.K.
      • Wachholz P.A.
      • Dearman R.J.
      • Kimber I.
      • Wurtzen P.A.
      • et al.
      The IgE-facilitated allergen binding (FAB) assay: validation of a novel flow-cytometric based method for the detection of inhibitory antibody responses.
      that remains popular today. The suppressive influence of ragweed injection immunotherapy on allergic inflammation in target organs was shown by Creticos et al.
      • Creticos P.S.
      • Marsh D.G.
      • Proud D.
      • Kagey-Sobotka A.
      • Adkinson Jr., N.F.
      • Friedhoff L.
      • et al.
      Responses to ragweed-pollen nasal challenge before and after immunotherapy.
      Passalacqua et al
      • Passalacqua G.
      • Albano M.
      • Fregonese L.
      • Riccio A.
      • Pronzato C.
      • Mela G.S.
      • et al.
      Randomised controlled trial of local allergoid immunotherapy on allergic inflammation in mite-induced rhinoconjunctivitis.
      similarly demonstrated decreased local eosinophilia and associated adhesion molecule expression during mite sublingual immunotherapy. Warner et al
      • Warner J.O.
      • Price J.F.
      • Soothill J.F.
      • Hey E.N.
      Controlled trial of hyposensitisation to Dermatophagoides pteronyssinus in children with asthma.
      and Rak et al
      • Rak S.
      • Björnson A.
      • Håkanson L.
      • Sörenson S.
      • Venge P.
      The effect of immunotherapy on eosinophil accumulation and production of eosinophil chemotactic activity in the lung of subjects with asthma during natural pollen exposure.
      observed decreases in allergen-induced late asthmatic responses and associated bronchial inflammation, respectively, in children and adults.
      Table IOne hundred years of allergen immunotherapy
      Author(s)MilestoneYear
      Noon
      • Noon L.
      Prophylactic inoculation against hayfever.
      First grass pollen subcutaneous immunotherapy trial1911
      Prausnitz and Küstner
      • Prausnitz C.
      • Küstner H.
      Studien über die Ueberempfindlichkeit.
      Passive serum transfer of immediate skin prick test reactivity “reagin”1921
      Freeman
      • Freeman J.
      Rush inoculation with special reference to hay fever treatment.
      First grass pollen rush immunotherapy trial1930
      Cooke et al
      • Cooke R.A.
      • Barnard J.H.
      • Hebald S.
      • Stull A.
      Serological immunity with co-existing sensitisation in a type of human allergy (hay fever).
      Concept of serum blocking antibodies1935
      Frankland and Augustin
      • Frankland A.W.
      • Augustin R.
      Prophylaxis of summer hayfever and asthma: controlled trial comparing crude grass pollen extracts with isolated main protein component.
      First double-blind, placebo-controlled, subcutaneous grass pollen immunotherapy trial1954
      Lowell and Franklin
      • Lowell F.C.
      • Franklin W.
      A double-blind study of the effectiveness and specificity of injection therapy in ragweed hay fever.
      Grass pollen effective in multiallergen mix subcutaneous immunotherapy1965
      Ishizaka et al
      • Ishizaka K.
      • Ishizaka T.
      • Hornbrook M.M.
      Physiochemical properties of reaginic antibody V. Correlation of reaginic activity with yEglobulin antibody.
      and Johansson and Bennich

      Johansson SGO, Bennich H. Studies on a new class of human immunoglobulins. 1. Immunological properties. Nobel symposium 3, gamma globulins, structure and control of biosynthesis. P193. (Stockholm, June 12-17, 1967.) Almqvist and Wiksell.

      Discovery of IgE antibody1966
      Johnstone and Dutton
      • Johnstone D.E.
      • Dutton A.
      The value of hyposensitization therapy for bronchial asthma in children-a 14-year study.
      Long-term benefits of subcutaneous immunotherapy in children1968
      Hunt et al
      • Hunt K.J.
      • Valentine M.D.
      • Sobotka A.K.
      • Benton A.W.
      • Amodio F.J.
      • Lichtenstein L.M.
      A controlled trial of immunotherapy in insect hypersensitivity.
      Efficacy of Hymenoptera venom vs whole-body extract subcutaneous immunotherapy1978
      Warner et al
      • Warner J.O.
      • Price J.F.
      • Soothill J.F.
      • Hey E.N.
      Controlled trial of hyposensitisation to Dermatophagoides pteronyssinus in children with asthma.
      Suppression of late asthmatic responses after mite immunotherapy1978
      Rocklin et al
      • Rocklin R.E.
      • Sheffer A.L.
      • Greineder D.K.
      • Melmon K.L.
      Generation of antigen-specific suppressor cells during allergy desensitization.
      Role of antigen-specific suppressor T cells in immunotherapy1980
      Gleich et al
      • Gleich G.J.
      • Zimmermann E.M.
      • Henderson L.L.
      • Yunginger J.W.
      Effect of immunotherapy on immunoglobulin E and immunoglobulin G antibodies to ragweed antigens: a six-year prospective study.
      Early increase in IgE level after ragweed subcutaneous immunotherapy, blunting of seasonal IgE1982
      Scadding and Brostoff
      • Scadding G.K.
      • Brostoff J.
      Low dose sublingual therapy in patients with allergic rhinitis due to house dust mite.
      First double-blind trial of sublingual immunotherapy1986
      Creticos et al
      • Creticos P.S.
      • Marsh D.G.
      • Proud D.
      • Kagey-Sobotka A.
      • Adkinson Jr., N.F.
      • Friedhoff L.
      • et al.
      Responses to ragweed-pollen nasal challenge before and after immunotherapy.
      Inhibition of allergic inflammation in the target organ after ragweed immunotherapy1989
      Rak et al
      • Rak S.
      • Björnson A.
      • Håkanson L.
      • Sörenson S.
      • Venge P.
      The effect of immunotherapy on eosinophil accumulation and production of eosinophil chemotactic activity in the lung of subjects with asthma during natural pollen exposure.
      Inhibition of late asthmatic responses after birch immunotherapy in adults1991
      Norman et al
      • Norman P.S.
      • Ohman Jr., J.L.
      • Long A.A.
      • Creticos P.S.
      • Gefter M.A.
      • Shaked Z.
      • et al.
      Treatment of cat allergy with T-cell reactive peptides.
      First T-cell peptide subcutaneous immunotherapy trial in patients with cat allergy1996
      Akdis et al
      • Akdis C.A.
      • Blesken T.
      • Akdis M.
      • Wüthrich B.
      • Blaser K.
      Role of interleukin 10 in specific immunotherapy.
      Role of IL-10 and regulatory T cells in venom immunotherapy1998
      Passalacqua et al
      • Passalacqua G.
      • Albano M.
      • Fregonese L.
      • Riccio A.
      • Pronzato C.
      • Mela G.S.
      • et al.
      Randomised controlled trial of local allergoid immunotherapy on allergic inflammation in mite-induced rhinoconjunctivitis.
      House dust mite allergoid sublingual immunotherapy1998
      Durham et al
      • Durham S.R.
      • Walker S.M.
      • Varga E.M.
      • Jacobson M.R.
      • O’Brien F.
      • Noble W.
      • et al.
      Long-term clinical efficacy of grass-pollen immunotherapy.
      Long-term clinical efficacy of grass pollen subcutaneous immunotherapy1999
      Niederberger et al
      • Niederberger V.
      • Horak F.
      • Vrtala S.
      • Spitzauer S.
      • Krauth M.T.
      • Valent P.
      • et al.
      Vaccination with genetically engineered allergens prevents progression of allergic disease.
      First trial of recombinant allergen subcutaneous immunotherapy in patients with birch allergy2004
      Creticos et al
      • Creticos P.S.
      • Schroeder J.T.
      • Hamilton R.G.
      • Balcer-Whaley S.L.
      • Khattignavong A.P.
      • Lindblad R.
      • et al.
      Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis.
      Ragweed Toll-like receptor 9 agonist subcutaneous immunotherapy2006
      Jacobsen
      • Jacobsen L.
      • Niggemann B.
      • Dreborg S.
      • Ferdousi H.A.
      • 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.
      Prevention of asthma after pollen subcutaneous immunotherapy in children (the PAT study)2007
      Durham et al
      • Durham S.R.
      • Emminger W.
      • Kapp A.
      • Colombo G.
      • de Monchy J.G.
      • Rak S.
      • et al.
      Long-term clinical efficacy in grass pollen-induced rhinoconjunctivitis after treatment with SQ-standardized grass allergy immunotherapy tablet.
      Long-term clinical efficacy of grass pollen sublingual immunotherapy2010
      The link between altered T-cell responses and immunotherapy was first highlighted by Rocklin et al,
      • Rocklin R.E.
      • Sheffer A.L.
      • Greineder D.K.
      • Melmon K.L.
      Generation of antigen-specific suppressor cells during allergy desensitization.
      who identified peripheral antigen-specific T suppressor cells after successful desensitization. Evidence for the critical role of regulatory T cells and IL-10 was highlighted by Akdis et al,
      • Akdis C.A.
      • Blesken T.
      • Akdis M.
      • Wüthrich B.
      • Blaser K.
      Role of interleukin 10 in specific immunotherapy.
      • Akdis C.A.
      • Akdis M.
      Mechanisms of allergen-specific immunotherapy.
      as well as Yamanaka et al,
      • Yamanaka K.
      • Yuta A.
      • Kakeda M.
      • Sasaki R.
      • Kitagawa H.
      • Gabazza E.C.
      • et al.
      Induction of IL-10-producing regulatory T cells with TCR diversity by epitope-specific immunotherapy in pollinosis.
      whereas the concept of a more delayed-in-time downregulation of allergen-specific CD4 TH2 responses in favor of TH1 responses in the periphery and in target organs has developed in parallel.
      • Varney V.A.
      • Hamid Q.A.
      • Gaga M.
      • Ying S.
      • Jacobson M.
      • Frew A.J.
      • et al.
      Influence of grass pollen immunotherapy on cellular infiltration and cytokine mRNA expression during allergen-induced late-phase cutaneous responses.
      • Ebner C.
      • Siemann U.
      • Bohle B.
      • Willheim M.
      • Wiedermann U.
      • Schenk S.
      • et al.
      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.
      • Durham S.R.
      • Ying S.
      • Varney V.A.
      • Jacobson M.R.
      • Sudderick R.M.
      • Mackay I.S.
      • et al.
      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.
      • Tulic M.K.
      • Fiset P.O.
      • Christodoulopoulos P.
      • Vaillancourt P.
      • Desrosiers M.
      • Lavigne F.
      • et al.
      Amb a 1-immunostimulatory oligodeoxynucleotide conjugate immunotherapy decreases the nasal inflammatory response.
      It remains unclear to what extent it is either altered memory T-cell responses, altered B-cell responses, or both that are responsible for the long-lived antigen-specific tolerance that characterizes successful allergen immunotherapy. This is in contrast to the short-lived symptomatic relief obtained with antiallergic drugs, such as antihistamines, or topical or oral corticosteroid treatment.

      Clinical developments

      Frankland
      • Frankland A.W.
      Immunotherapy [allergy archives].
      summarizes clinical developments in immunotherapy over the past 100 years. After the death of Leonard Noon from tuberculosis the same year as his seminal publication, his colleague John Freeman extended observations on pollen immunotherapy to include documentation of seasonal symptoms and the introduction of modified immunotherapy protocols, including the first rush protocol in 1928.
      • Freeman J.
      Rush inoculation with special reference to hay fever treatment.
      The first double-blind controlled trial of pollen immunotherapy was published by Frankland and Augustin
      • Frankland A.W.
      • Augustin R.
      Prophylaxis of summer hayfever and asthma: controlled trial comparing crude grass pollen extracts with isolated main protein component.
      in 1954 and established a firm scientific foundation for the further development of allergen immunotherapy. Frankland was a founding member of the British Allergy Society, and in his 99th year, he remains very active within the allergy community in the United Kingdom.
      The practice in the United States of multiple-allergen immunotherapy is in contrast to the usual practice in Europe.
      • Cox Calderon M.A.
      Subcutaneous specific immunotherapy for seasonal allergic rhinitis: a review of treatment practices in the US and Europe.
      The elegant study of Lowell and Franklin
      • Lowell F.C.
      • Franklin W.
      A double-blind study of the effectiveness and specificity of injection therapy in ragweed hay fever.
      in 1964 was the first to clearly demonstrate that a single allergen (ragweed) in a multiallergen mixture was effective in reducing seasonal allergic symptoms. Norman and Lichtenstein
      • Norman P.S.
      • Lichtenstein L.M.
      The clinical and immunologic specificity of immunotherapy.
      were the first to demonstrate the allergen specificity of ragweed immunotherapy. The results of one double-blind placebo-controlled trial of multiallergen immunotherapy in children was disappointing.
      • Adkinson Jr., N.F.
      • Eggleston P.A.
      • Eney D.
      • Goldstein E.O.
      • Schuberth K.C.
      • Bacon J.R.
      • et al.
      A controlled trial of immunotherapy for asthma in allergic children.
      Further controlled trials with a more inclusive mix of relevant allergens in defined allergic populations are required. Johnstone and Dutton
      • Johnstone D.E.
      • Dutton A.
      The value of hyposensitization therapy for bronchial asthma in children-a 14-year study.
      first highlighted the possibility that immunotherapy in children conferred long-term benefits. This concept is supported by a more recent randomized controlled trial of 3 years of pollen injection immunotherapy in children with hay fever in whom a 2- to 3-fold reduction in the risk of progression from rhinitis to asthma was observed that persisted for up to 7 years after discontinuation of treatment.
      • Jacobsen L.
      • Niggemann B.
      • Dreborg S.
      • Ferdousi H.A.
      • 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.
      The corticosteroid dose in asthmatic children has also been reported to be reduced on immunotherapy.
      • Zielen S.
      • Kardos P.
      • Madonini E.
      Steroid-sparing effects with allergen-specific immunotherapy in children with asthma: a randomized controlled trial.
      The duration of immunotherapy (3 vs 5 years) needed for optimal clinical improvement, however, is not established.
      • Tabar A.I.
      • Echechipia S.
      • Garcia B.E.
      • Martin S.
      • Alvarez-Puebla M.J.
      • Arroabarren E.
      Three years of specific immunotherapy may be sufficient in house dust mite respiratory allergy.
      Hunt et al
      • Hunt K.J.
      • Valentine M.D.
      • Sobotka A.K.
      • Benton A.W.
      • Amodio F.J.
      • Lichtenstein L.M.
      A controlled trial of immunotherapy in insect hypersensitivity.
      demonstrated the efficacy of purified venom over insect whole-body extract and placebo in patients with anaphylaxis to the stings of Hymenoptera.

      Guidelines

      The World Health Organization position paper published in 1998 made recommendations regarding major allergen content for the efficacy of immunotherapy.
      • Bousquet J.
      • Lockey R.
      • Malling H.J.
      Allergen immunotherapy: therapeutic vaccines for allergic diseases. A WHO position paper.
      A major advance since 1980 has been attempts to standardize the allergen content of extracts for both diagnosis and immunotherapy in terms of both biological potency and content of major allergen. Several dose-response studies calculated on the basis of major allergen content have confirmed the dose dependency of immunotherapy in both phase II provocation studies
      • 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.
      • Nanda A.
      • O’connor M.
      • Anand M.
      • Dreskin S.C.
      • Zhang L.
      • Hines B.
      • et al.
      Dose dependence and time course of the immunologic response to administration of standardized cat allergen extract.
      and phase III trials.
      • Durham S.R.
      • Yang W.H.
      • Pedersen M.R.
      • Johansen N.
      • Rak S.
      Sublingual immunotherapy with once-daily grass allergen tablets: a randomized controlled trial in seasonal allergic rhinoconjunctivitis.
      • Didier A.
      • Malling H.J.
      • Worm M.
      • Horak F.
      • Jäger S.
      • Montagut A.
      • et al.
      Optimal dose, efficacy, and safety of once-daily sublingual immunotherapy with a 5-grass pollen tablet for seasonal allergic rhinitis.
      • Frew A.J.
      • Powell R.J.
      • Corrigan C.J.
      • Durham S.R.
      Efficacy and safety of specific immunotherapy with SQ allergen extract in treatment-resistant seasonal allergic rhinoconjunctivitis.
      The CREATE project, under the guidance of van Ree
      • van Ree R.
      The CREATE partnership
      The CREATE project: EU support for the improvement of allergen standardization in Europe.
      and Chapman et al,
      • Chapman M.D.
      • Ferreira F.
      • Villalba M.
      • Cromwell O.
      • Bryan D.
      • Becker W.M.
      • et al.
      The European Union CREATE project: a model for international standardization of allergy diagnostics and vaccines.
      has resulted in the availability of several standardized allergens and laboratory assays for measurement of allergen content that should facilitate more effective standardization of extracts. Dose recommendations for US practitioners are given in the practice parameters published in this issue.
      • Cox L.S.
      • Nelson H.
      • Lockey R.
      • Calabria C.
      • Chacko T.
      • Fingegold I.
      • et al.
      Allergen immunotherapy: a practice parameter third update.
      Continued effective cooperation among academia, industry, and regulatory agencies is necessary for further progress.
      After the World Health Organization report, the Cochrane Collaboration has provided rigorous scientific evaluation and expanded the evidence base in favor of immunotherapy,
      • Abramson M.J.
      • Puy R.M.
      • Weiner J.M.
      Allergen immunotherapy for asthma. An update.
      • Calderon M.A.
      • Alves B.
      • Jacobson M.
      • Hurwitz B.
      • Sheikh A.
      • Durham S.
      Allergen injection immunotherapy for seasonal allergic rhinitis.
      • Wilson D.R.
      • Torres-Lima M.
      • Durham S.R.
      Sublingual immunotherapy for allergic rhinitis: systematic review and meta-analysis.
      although the limitations of meta-analysis in terms of the heterogeneity of included studies and the possibility of positive publication bias are acknowledged.
      • Nieto A.
      • Mazon A.
      • Pamies R.
      • Bruno L.
      • Navarro M.
      • Montanes A.
      Sublingual immunotherapy for allergic respiratory diseases: an evaluation of meta-analyses.
      Recent advances include the Grades of Recommendation, Assessment, Development and Evaluation approach, which focuses more critically on actual clinical value and cost effectiveness.
      • Brozek J.L.
      • Bousquet J.
      • Baena-Cagnani C.E.
      • Bonini S.
      • Canonica G.W.
      • Casale T.B.
      • et al.
      Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision.
      The availability of standardized allergen extracts has permitted dose-response studies that have informed more definitive phase III trials. The World Allergy Organization has provided guidelines to optimize clinical trial design,
      • Canonica G.W.
      • Baena-Cagnani C.E.
      • Bousquet J.
      • Bousquet P.J.
      • Lockey R.F.
      • Malling H.J.
      • et al.
      Recommendations for standardization of clinical trials with Allergen Specific Immunotherapy for respiratory allergy. A statement of a World Allergy Organization (WAO) taskforce.
      and the GA2LEN collaboration has provided advice on proper reporting according to the Consolidated Standards of Reporting Trials criteria.
      • Bousquet P.J.
      • Brozek J.
      • Bachert C.
      • Bieber T.
      • Bonini S.
      • Burney P.
      • et al.
      The CONSORT statement checklist in allergen-specific immunotherapy: a GA2LEN paper.
      • Bousquet P.J.
      • Calderon M.A.
      • Demoly P.
      • Larenas D.
      • Passalacqua G.
      • Bachert C.
      • et al.
      The CONSORT statement applied to allergen-specific immunotherapy with inhalant allergens. A GA2LEN paper.
      These issues are discussed in the article by Calderon et al.
      • Calderon M.
      • Casale T.B.
      • Togias A.
      • Bousquet J.
      • Durham S.R.
      • Demoly P.
      Allergen-specific immunotherapy for respiratory allergies: from meta-analysis to registration and beyond.
      The recent “big trials” have clearly defined the value of both subcutaneous and sublingual immunotherapy in adults and children
      • Wahn U.
      • Tabar A.
      • Kuna P.
      • Halken S.
      • Montagut A.
      • de Beaumont O.
      • et al.
      Efficacy and safety of 5-grass-pollen sublingual immunotherapy tablets in pediatric allergic rhinoconjunctivitis.
      • Bufe A.
      • Eberle P.
      • Franke-Beckmann E.
      • Funck J.
      • Kimmig M.
      • Klimek L.
      • et al.
      Safety and efficacy in children of an SQ-standardized grass allergen tablet for sublingual immunotherapy.
      with seasonal pollinosis, including identification of optimal doses
      • 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.
      • Nanda A.
      • O’connor M.
      • Anand M.
      • Dreskin S.C.
      • Zhang L.
      • Hines B.
      • et al.
      Dose dependence and time course of the immunologic response to administration of standardized cat allergen extract.
      and the optimal preseasonal duration of sublingual immunotherapy.
      • Calderon M.A.
      • Birk A.O.
      • Andersen J.S.
      • Durham S.R.
      Prolonged preseasonal treatment phase with Grazax sublingual immunotherapy increases clinical efficacy.
      In this issue Cox et al
      • Cox L.S.
      • Nelson H.
      • Lockey R.
      • Calabria C.
      • Chacko T.
      • Fingegold I.
      • et al.
      Allergen immunotherapy: a practice parameter third update.
      provide a comprehensive third update to their practice parameters for immunotherapy. Highlights include an algorithm for the key decision points for the use of immunotherapy and a new classification and grading of systemic reactions that should facilitate a more accurate and standardized method for reporting side effects. Controversial issues, such as circumstances in which concomitant use of β-blockers might be reasonable and whether to recommend a prophylactic adrenaline autoinjector to patients undergoing immunotherapy, are carefully considered. Hankin and Lockey
      • Hankin C.
      • Lockey R.F.
      Patient characteristics associated with allergen immunotherapy initiation and adherence.
      discuss patient adherence to immunotherapy. Sadly, the main conclusion is the lack of data in contrast to studies evaluating compliance with pharmacologic treatment. Hankin and Lockey highlight several simple approaches that could be pursued, and this must surely represent an opportunity for professional organizations to support studies to evaluate adherence to improve patient selection for immunotherapy and outcomes. Lockey and Hankin
      • Lockey R.F.
      • Hankin C.
      Health economics of allergen specific immunotherapy in the United States of America.
      review the limited data available from the United States and elsewhere concerning the economic costs of immunotherapy. Although acknowledging the methodologic shortcomings of these studies and the need for more robust data, they conclude that subcutaneous immunotherapy is associated with significant health care savings, with one study showing up to an 80% reduction in health costs at 3 years after completion of treatment.

      Sublingual immunotherapy

      After the first double-blind trial in mite-sensitive adults,
      • Scadding G.K.
      • Brostoff J.
      Low dose sublingual therapy in patients with allergic rhinitis due to house dust mite.
      sublingual immunotherapy has emerged as an effective alternative to the subcutaneous route and is widely practiced in Europe, although at present to a lesser extent in the United States.
      • Canonica G.W.
      • Bousquet J.
      • Casale T.
      • Lockey R.F.
      • Baena-Cagnani C.E.
      • Pawankar R.
      • et al.
      Sub-lingual immunotherapy: World Allergy Organization Position Paper 2009.
      • Cox L.S.
      • Larenas Linnemann D.
      • Nolte H.
      • Weldon D.
      • Finegold I.
      • Nelson H.S.
      Sublingual immunotherapy: a comprehensive review.
      Unlike subcutaneous immunotherapy, sublingual immunotherapy might act primarily through its effects on oral Langerhans cells.
      • Larche M.
      Immune mechanisms of sublingual immunotherapy: are oral Langerhans cells the masters of tolerance?.
      Several published definitive trials of grass pollen tablets have confirmed their efficacy, safety, and tolerability in both adults and children.
      • Durham S.R.
      • Yang W.H.
      • Pedersen M.R.
      • Johansen N.
      • Rak S.
      Sublingual immunotherapy with once-daily grass allergen tablets: a randomized controlled trial in seasonal allergic rhinoconjunctivitis.
      • Didier A.
      • Malling H.J.
      • Worm M.
      • Horak F.
      • Jäger S.
      • Montagut A.
      • et al.
      Optimal dose, efficacy, and safety of once-daily sublingual immunotherapy with a 5-grass pollen tablet for seasonal allergic rhinitis.
      • Wahn U.
      • Tabar A.
      • Kuna P.
      • Halken S.
      • Montagut A.
      • de Beaumont O.
      • et al.
      Efficacy and safety of 5-grass-pollen sublingual immunotherapy tablets in pediatric allergic rhinoconjunctivitis.
      • Bufe A.
      • Eberle P.
      • Franke-Beckmann E.
      • Funck J.
      • Kimmig M.
      • Klimek L.
      • et al.
      Safety and efficacy in children of an SQ-standardized grass allergen tablet for sublingual immunotherapy.
      The sublingual route appears safe and has broadened the availability of immunotherapy to include self-administration, although continued vigilance after registration of products in Europe is ongoing and a proper standardized reporting system for side effects of sublingual immunotherapy is required. The repertoire of large sublingual studies needs to be extended to include seasonal allergens other than grass and also perennial allergens, including mites, molds, cockroach, and animal dander. If safety and tolerability continue to be acceptable, this should allow a broadening of the evaluations from rhinitis to include asthma, eczema,
      • Dahl R.
      • Stender A.
      • Rak S.
      Specific immunotherapy with SQ standardized grass allergen tablets in asthmatics with rhinoconjunctivitis.
      • Bussmann C.
      • Böckenhoff A.
      • Henke H.
      • Werfel T.
      • Novak N.
      Does allergen-specific immunotherapy represent a therapeutic option for patients with atopic dermatitis?.
      and food allergies. In the case of food allergies, there have also been several studies suggesting a beneficial effect of oral immunotherapy,
      • Narisety S.D.
      • Skripak J.M.
      • Steele P.
      • Hamilton R.G.
      • Matsui E.C.
      • Burks A.W.
      • et al.
      Open-label maintenance after milk oral immunotherapy for IgE-mediated cow’s milk allergy.
      • Jones S.M.
      • Pons L.
      • Roberts J.L.
      • Scurlock A.M.
      • Perry T.T.
      • Kulis M.
      • et al.
      Clinical efficacy and immune regulation with peanut oral immunotherapy.
      • Blumchen K.
      • Ulbricht H.
      • Staden U.
      • Dobberstein K.
      • Beschorner J.
      • de Oliveira L.C.
      • et al.
      Oral peanut immunotherapy in children with peanut anaphylaxis.
      but further studies are required to establish the safety and efficacy of this approach, particularly in patients with peanut allergy.
      • Thyagarajan A.
      • Varshney P.
      • Jones S.M.
      • Sicherer S.
      • Wood R.
      • Vickery B.P.
      • et al.
      Peanut oral immunotherapy is not ready for clinical use.
      • Varshney P.
      • Steele P.H.
      • Vickery B.P.
      • Bird J.A.
      • Thyagarajan A.
      • Scurlock A.M.
      • et al.
      Adverse reactions during peanut oral immunotherapy home dosing.
      It is noteworthy that unlike the Lowell and Franklin
      • Lowell F.C.
      • Franklin W.
      A double-blind study of the effectiveness and specificity of injection therapy in ragweed hay fever.
      study of subcutaneous immunotherapy reported above, grass pollen sublingual immunotherapy was ineffective when administered as part of a multiallergen mix,
      • Amar S.M.
      • Harbeck R.J.
      • Sills M.
      • Silveira L.J.
      • O’Brien H.
      • Nelson H.S.
      Response to sublingual immunotherapy with grass pollen extract: monotherapy versus combination in a multiallergen extract.
      which questions the likely value of multiallergen sublingual immunotherapy in contrast to the single-allergen approach favored in Europe. There is a need to evaluate more patient-centered outcomes and cost-effectiveness of the sublingual approach, as addressed by Canonica and Passalaqua
      • Canonica W.G.
      • Passalacqua G.
      Disease modifying effect and economic implications of sublingual immunotherapy.
      in their article.

      Long-term benefits

      The demonstration of clinical and immunologic tolerance to seasonal pollens
      • Durham S.R.
      • Walker S.M.
      • Varga E.M.
      • Jacobson M.R.
      • O’Brien F.
      • Noble W.
      • et al.
      Long-term clinical efficacy of grass-pollen immunotherapy.
      (persistence of benefit for several years after discontinuation of immunotherapy) and the possibility that pollen immunotherapy might reduce progression to asthma
      • Jacobsen L.
      • Niggemann B.
      • Dreborg S.
      • Ferdousi H.A.
      • 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.
      and prevent new sensitizations
      • Des Roches A.
      • Paradis L.
      • Menardo J.-L.
      • Bouges S.
      • Daures J.-P.
      • Bousquet J.
      Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. VI. Specific immunotherapy prevents the onset of new sensitizations in children.
      are reviewed by Canonica and Passalaqua.
      • Canonica W.G.
      • Passalacqua G.
      Disease modifying effect and economic implications of sublingual immunotherapy.
      These observations raise the question of whether immunotherapy should be introduced earlier in the course of allergic disease, as suggested in the recent World Allergy Organization position paper, rather than be restricted to those patients who do not respond to the usual antiallergic drugs or those who experience unacceptable side effects of pharmacotherapy. One recent large double-blind trial of grass pollen tablets has confirmed long-term remission after 3 years of immunotherapy.
      • Durham S.R.
      • Emminger W.
      • Kapp A.
      • Colombo G.
      • de Monchy J.G.
      • Rak S.
      • et al.
      Long-term clinical efficacy in grass pollen-induced rhinoconjunctivitis after treatment with SQ-standardized grass allergy immunotherapy tablet.
      A recent open, partially randomized study of mite immunotherapy suggested that 4 rather than 3 years of sublingual immunotherapy might be optimal for long-term tolerance.
      • Marogna M.
      • Spadolini I.
      • Massolo A.
      • Canonica G.W.
      • Passalacqua G.
      Long-lasting effects of sublingual immunotherapy according to its duration: a 15-year prospective study.
      Further large, double-blind, randomized trials are needed to rigorously test the preventive effects of immunotherapy on the development of new sensitizations and disease progression before firm recommendations can be made.

      Novel approaches and future directions

      Casale and Stokes
      • Casale T.B.
      • Stokes J.R.
      Future forms of immunotherapy.
      herein review novel approaches to immunotherapy, commencing with the use of subcutaneous allergen in combination with anti-IgE treatment. Other approaches summarized include peptide immunotherapy that uses short, linear T-cell epitopes that retain immunogenicity while losing the potential to cross-link IgE and induce anaphylaxis.
      • Norman P.S.
      • Ohman Jr., J.L.
      • Long A.A.
      • Creticos P.S.
      • Gefter M.A.
      • Shaked Z.
      • et al.
      Treatment of cat allergy with T-cell reactive peptides.
      • Oldfield W.L.
      • Larche M.
      • Kay A.B.
      Effect of T-cell peptides derived from Fel d 1 on allergic reactions and cytokine production in patients sensitive to cats: a randomised controlled trial.
      Allergoids are an alternative attempt to reduce allergenicity,
      • Corrigan C.J.
      • Kettner J.
      • Doemer C.
      • Cromwell O.
      • Narkus A.
      Study Group
      Efficacy and safety of preseasonal-specific immunotherapy with an aluminium-adsorbed six-grass pollen allergoid.
      whereas adjuvants such as CpG-containing bacterial DNA fragments
      • Creticos P.S.
      • Schroeder J.T.
      • Hamilton R.G.
      • Balcer-Whaley S.L.
      • Khattignavong A.P.
      • Lindblad R.
      • et al.
      Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis.
      and bacterial cell wall LPSs (MPL)
      • Drachenberg K.J.
      • Wheeler A.W.
      • Stuebner P.
      • Horak F.
      A well tolerated grass pollen- specific allergy vaccine containing a novel adjuvant, monophosphoryl lipid A, reduces allergic symptoms after only four preseasonal injections.
      combined with allergen have been shown to be effective in inducing immune deviation and suppressing symptoms. The recent successful development of recombinant wild-type
      • Jutel M.
      • Jäger L.
      • Suck R.
      • Meyer H.
      • Fiebig H.
      • Cromwell O.
      Allergen-specific immunotherapy with recombinant grass pollen allergens.
      • Pauli G.
      • Larsen T.H.
      • Rak S.
      • Horak F.
      • Pastorello E.
      • Valenta R.
      • et al.
      Efficacy of recombinant birch pollen vaccine for the treatment of birch-allergic rhinoconjunctivitis.
      and modified
      • Niederberger V.
      • Horak F.
      • Vrtala S.
      • Spitzauer S.
      • Krauth M.T.
      • Valent P.
      • et al.
      Vaccination with genetically engineered allergens prevents progression of allergic disease.
      allergens holds promise in terms of optimal standardization and the potential for personalized immunotherapy tailored to individual IgE sensitivities.
      • Valenta R.
      • Ferreira F.
      • Focke-Tejkl M.
      • Linhart B.
      • Niederberger V.
      • Swoboda I.
      • et al.
      From allergen genes to allergy vaccines.
      The use of intra–lymph node injections of allergen
      • Senti G.
      • Prinz Vavricka B.M.
      • Erdmann I.
      • Diaz M.I.
      • Markus R.
      • McCormack S.J.
      • et al.
      Intralymphatic allergen administration renders specific immunotherapy faster and safer: a randomized controlled trial.
      and, more recently, of allergen-containing patches for transdermal use
      • Senti G.
      • Graf N.
      • Haug S.
      • Rüedi N.
      • von Moos S.
      • Sonderegger T.
      • et al.
      Epicutaneous allergen administration as a novel method of allergen-specific immunotherapy.
      have stimulated great interest.
      The jewel in the crown of allergen immunotherapy is its ability to induce long-term tolerance (ie, clinical efficacy after its discontinuation). The demonstration that both the subcutaneous and sublingual routes might induce tolerance should broaden the indications for immunotherapy in the future.
      • Scadding G.K.
      • Brostoff J.
      Low dose sublingual therapy in patients with allergic rhinitis due to house dust mite.
      Novel approaches, including the sublingual route, that achieve tolerance effectively,
      • Larche M.
      • Akdis C.A.
      • Valenta R.
      Immunological mechanisms of allergen specific immunotherapy.
      • Scadding G.
      • Durham S.
      Mechanisms of sublingual immunotherapy.
      safely, and in a more convenient and cost-effective manner require enthusiastic support and further development rather than a continued reliance on the current traditional subcutaneous immunotherapy with its acknowledged limitations. The progress made in these past 100 years of immunotherapy combined with new technologic and scientific advances on the horizon portend dramatic changes for the next 100 years (Fig 1).

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