Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Safety Profile of Sublingual Immunotherapy

Abstract

Sublingual immunotherapy (SLIT) was proposed for clinical practice about 20 years ago with the main aim of improving the safety and avoiding the adverse effects of traditional treatment for allergic airways disease. To date, 32 randomized controlled trials and 6 postmarketing surveys have been published that provide a robust documentation of the safety profile of the treatment.

Looking at the randomized trials it emerges that the more frequent adverse event of SLIT is oral itching or swelling, followed by gastrointestinal complaints. These adverse events are invariably described as mild and easily managed by adjusting the dose. Relevant systemic adverse events (asthma, urticaria, angioedema) occur sporadically and, with the exception of oral/gastrointestinal adverse events, the incidence of adverse events seems not to differ between the placebo and active groups. The safety profile of SLIT does not differ between adults and children.

The postmarketing surveys consistently show that the incidence of adverse events associated with SLIT is less than 10%, corresponding to less than 1 adverse event per 1000 doses, and is thus quite superior to the safety profile of subcutaneous immunotherapy. Of note, the most recent data show that the rate of adverse events with SLIT is not increased in children below the age of 5 years.

This is a preview of subscription content, log in to check access.

Table I
Table II

References

  1. 1.

    Noon L. Prophylactic inoculation against hay fever. Lancet 1911; I: 1572–3

  2. 2.

    Black JH. The oral administration of pollen. J Lab Clin Med 1927; 12: 1156

  3. 3.

    Herxeimer H. Bronchial hypersensitization and hyposensitization in man. Int Arch Allergy Appl Immunol 1951; 40: 40–57

  4. 4.

    Taylor G, Shivalkar PR. Local nasal desensitization in allergic rhinitis. Clin Allergy 1972; 2: 125–6

  5. 5.

    Taudorf E, Weeke B. Orally administered grass pollen. Allergy 1983; 38: 561–4

  6. 6.

    Passalacqua G, Berardi M, Baena-Cagnani CE, et al. Oral and sublingual immunotherapy in pediatric patients. Curr Opin Allergy Immunol 2003; 3: 139–45

  7. 7.

    Committee on the Safety of Medicines. CSM update: desensitizing vaccines. BMJ 1986; 293: 948

  8. 8.

    Scadding K, Brostoff J. Low dose sublingual therapy in patients with allergic rhinitis due to dust mite. Clin Allergy 1986; 16: 483–91

  9. 9.

    Lockey RF, Benedict LM, Turkeltaub PC, et al. Fatalities from immunotherapy and skin testing. J Allergy Clin Immunol 1987; 79: 660–77

  10. 10.

    Reid MJ, Lockey RF, Turkeltaub PC, et al. Survey of fatalities from skin testing and immunotherapy. J Allergy Clin Immunol 1993; 92: 6–15

  11. 11.

    Mailing HJ, Weeke B, editors. EAACI immunotherapy position paper. Allergy 1993; 48 Suppl. 44: S64

  12. 12.

    Canonica GW, Passalacqua G. Non injection routes for immunotherapy. J Allergy Clin Immunol 2003; 111: 437–48

  13. 13.

    Bousquet J, Lockey R, Mailing HJ, editors. World Health Organization position paper. Allergen immunotherapy: therapeutical vaccines for allergic diseases. Allergy 1998; 53(Suppl. 54): S3–10

  14. 14.

    Mailing HJ, editor. EAACI position paper on local immunotherapy. Allergy 1998; 53: 933–44

  15. 15.

    Bousquet J, Van Cauwenberge P, editors. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol 2001; 108(5 Suppl.): S146–50

  16. 16.

    Muller U, Mosbech H. Immunotherapy with hymenoptera venom. Position paper. Allergy 1993; 48 Suppl. 14: 9–35

  17. 17.

    Moller C, Dreborg S, Lanner A, et al. Oral immunotherapy of children with rhinoconjunctivitis due to birch pollen allergy. Allergy 1986; 41: 271–9

  18. 18.

    Taudorf E, Laursen CL, Lanner A, et al. Oral immunotherapy to birch pollen hay fever. J Allergy Clin Immunol 1987; 80: 153–61

  19. 19.

    Mosbech H, Dreborg S, Madsenn F, et al. High dose grass pollen tablets used for hyposensitization in hay fever patients: a one year double blind placebo controlled study. Allergy 1987; 42: 451–5

  20. 20.

    Mailing HJ. Immunotherapy as an effective tool in allergy treatment. Allergy 1998; 53: 461–72

  21. 21.

    Tari MG, Mancino M, Monti G. Efficacy of sublingual immunotherapy in patients with rhinitis and asthma due to house dust mite: a double blind study. Allergol Immunopathol (Madr) 1990; 18: 277–84

  22. 22.

    Sabbah A, Hassoun S, Le Sellin J, et al. A double blind placebo controlled trial by the sublingual route of immunotherapy with a standardized grass pollen extract. Allergy 1994; 49: 309–13

  23. 23.

    Feliziani V, Lattuada G, Parmiani S, et al. Safety and efficacy of sublingual rush immunotherapy with grass allergen extracts: a double blind study. Allergol Immunopathol (Madr) 1995; 23: 173–8

  24. 24.

    Troise C, Voltolini S, Canessa A, et al. Sublingual immunotherapy in parietaria pollen induced rhinitis: a double blind study. J Invest Allergol Clin Immunol 1995; 5: 25–30

  25. 25.

    Hirsch T, Sahn M, Leupold W. Double blind placebo controlled study of sublingual immunotherapy with house dust mite extracts in children. Pediatr Allergy Immunol 1997; 8: 21–7

  26. 26.

    Clavel R, Bousquet J, Andre’ C. Clinical efficacy of sublingual swallow immunotherapy: a double blind placebo controlled trial of a standardized five grass pollen extract in rhinitis. Allergy 1998; 53: 493–8

  27. 27.

    Horak F, Stubner UE, Berger U, et al. Immunotherapy with sublingual birch pollen extract: a short term double blind study. J Invest Allergol Clin Immunol 1998; 8: 165–71

  28. 28.

    Vourdas D, Syrigou E, Potamianou P, et al. Double blind placebo controlled evaluation of sublingual immunotherapy with a standardized olive tree pollen extract in pediatric patients with allergic rhinoconjunctivitis and mild asthma due to olive tree pollen sensitization. Allergy 1998; 53: 662–71

  29. 29.

    Hordijk GJ, Antwelink JB, Luwema RA. Sublingual immunotherapy with a standardized grass pollen extract: a double blind placebo controlled study. Allergol Immunopathol (Madr) 1998; 26: 234–40

  30. 30.

    Passalacqua G, Albano M, Fregonese L, et al. Randomised controlled trial of local allergoid immunotherapy on allergic inflammation in mite induced rhinoconjunctivitis. Lancet 1998; 351: 629–32

  31. 31.

    Passalacqua G, Albano M, Riccio AM, et al. Clinical and immunological effects of a rush sublingual immunotherapy to parietaria species: a double blind placebo controlled trial. J Allergy Clin Immunol 1999; 104: 964–8

  32. 32.

    Bousquet J, Scheinmann P, Guinnepain MT, et al. Sublingual swallow immunotherapy (SLIT) in patients with asthma due to house dust mites: a double blind placebo controlled study. Allergy 1999; 54: 249–60

  33. 33.

    Purello D’Ambrosio F, Gangemi S, Isola S, et al. Sublingual immunotherapy: a double blind placebo controlled trial with Parietaria judaica extract standardized in mass units in patients with rhinoconjunctivitis, asthma or both. Allergy 1999; 54: 968–73

  34. 34.

    Pradalier A, Basset D, Claudel A, et al. Sublingual swallow immunotherapy (SLIT) with a standardized five grass pollen extract (drops and sublingual tablets) versus placebo in seasonal rhinitis. Allergy 1999; 54: 819–28

  35. 35.

    La Rosa M, Ranno C, André C, et al. Double blind placebo controlled evaluation of sublingual swallow immunotherapy with standardized Parietaria judaica extract in children with allergic rhinoconjunctivitis. J Allergy Clin Immunol 1999; 104: 425–32

  36. 36.

    Guez S, Vatrinet C, Fadel R, et al. House dust mite sublingual swallow immunotherapy in perennial rhinitis: a double blind placebo controlled study. Allergy 2000; 55: 369–75

  37. 37.

    Pajno GB, Morabito L, Barberio G, et al. Clinical and immunological effects of longterm sublingual immunotherapy in asthmatic children sensitized to mite: a double blind study. Allergy 2000; 55: 842–9

  38. 38.

    Caffarelli C, Sensi LG, Marcucci F, et al. Preseasonal local allergoid immunotherapy to grass pollen in children: a double-blind, placebo-controlled, randomized trial. Allergy. 2000; 55: 1142–7

  39. 39.

    Ariano R, Spadolini I, Panzani RC. Efficacy of sublingual specific immunotherapy in Cupressaceae allergy using an extract of Cupressus arizonica: a double blind study. Allergol Immunopathol (Madr) 2001; 29: 238–44

  40. 40.

    Bahceciler NN, Isik U, Barlan IB, et al. Efficacy of sublingual immunotherapy in children with asthma and rhinitis: a double-blind, placebo-controlled study. Pediatr Pulmonol 2001; 32: 49–55

  41. 41.

    Voltolini S, Modena P, Minale P, et al. Sublingual immunotherapy in tree pollen allergy: double blind, placebo controlled study with a biologically standardized extract of tree pollen (alder, birch and hazel) administered by a rush schedule. Allergol Immunopathol 2001; 29: 103–10

  42. 42.

    Lima MT, Wilson D, Pitkin L, et al. Grass pollen sublingual immunotherapy for seasonal rhinoconjunctivitis: a randomized controlled trial. Clin Exp Allergy 2002; 32: 507–14

  43. 43.

    Mortemousque B, Bertel F, De Casamayor J, et al. House-dust mite sublingual-swallow immunotherapy in perennial conjunctivitis: a double-blind, placebo-controlled study. Clin Exp Allergy 2003; 33: 464–9

  44. 44.

    André C, Perrin-Fayolle M, Grosclaude M, et al. A double blind placebo controlled evaluation of SLIT with a standardized ragweed extract in patients with seasonal rhinitis. Int Arch Allergy Immunol 2003; 131: 111–8

  45. 45.

    Ippoliti F, De Sanctis W, Volterrani A, et al. Immunomodulation during sublingual therapy in allergic children. Pediatr Allergy Immunol 2003; 14: 216–21

  46. 46.

    Pajno G, Vita D, Caminiti D, et al. 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 Dec; 33(12): 1641–7

  47. 47.

    Wuthrich B, Bucher CH, Jorg W, et al. Double-blind, placebo-controlled study with sublingual immunotherapy in children with seasonal allergic rhinitis to grass pollen. J Investig Allergol Clin Immunol 2003; 13(3): 145–8

  48. 48.

    Tonnel AB, Scherpereel A, Douay B, et al. Allergic rhinitis due to house dust mites: evaluation of the efficacy of specific sublingual immunotherapy. Allergy 2004 May; 59(5): 491–7

  49. 49.

    Bufe A, Ziegler-Kirbach E, Stoeckmann E, et al. Efficacy of sublingual swallow immunotherapy in children with severe grass pollen allergic symptoms: a double-blind placebo-controlled study. Allergy 2004; 59: 498–504

  50. 50.

    Smith H, White P, Annila I, et al. Randomized controlled trial of high-dose sublingual immunotherapy to treat seasonal allergic rhinitis. J Allergy Clin Immunol 2004; 114: 831–7

  51. 51.

    Rolinck-Werninghaus C, Wolf H, Liebke C, et al. A prospective, randomized, double-blind, placebo-controlled multi-centre study on the efficacy and safety of sublingual immunotherapy (SLIT) in children with seasonal allergic rhinoconjunctivitis to grass pollen. Allergy 2004; 59: 1285–93

  52. 52.

    Bowen T, Greenbaum J, Charbonneau Y, et al. Canadian trial of sublingual swallow immunotherapy for ragweed rhinoconjunctivitis. Ann Allergy Asthma Immunol 2004; 93: 425–30

  53. 53.

    André C, Vatrinet C, Galvain S, et al. Safety of sublingual swallow immunotherapy in children and adults. Int Arch Allergy Immunol 2000; 121: 229–34

  54. 54.

    Di Rienzo V, Pagani A, Parmiani S, et al. Post-marketing surveillance study on the safety of sublingual immunotherapy in children. Allergy 1999; 54: 1110–3

  55. 55.

    Lombardi C, Gargioni S, Melchiorre A, et al. Safety of sublingual immunotherapy in adults: a post marketing surveillance study. Allergy 2001; 56: 889–92

  56. 56.

    Pajno GB, Peroni DG, Vita D, et al. Safety of sublingual immunotherapy in children with asthma. Paediatr Drugs 2003; 5: 777–81

  57. 57.

    Drachenberg KJ, Urban E, Proll S, et al. Sublingual specific immunotherapy for adults and children: a post marketing survey. Allergol Immunopathol (Madr) 2004; 32: 76–81

  58. 58.

    Agostinis F, Tellarini L, Canonica GW, et al. Safety of SLIT in very young children. Allergy 2005; 60: 133

  59. 59.

    Di Rienzo V, Musarra A, Sambugaro R, et al. Post marketing survey on the safety of sublingual immunotherapy in children below the age of 5 years [abstract no. 153]. V National Congress of the Italian Society of Respiratory Medicine; 2004, Milan

  60. 60.

    Almagro E, Assensio O, Bartolomé JM, et al. Estudio multicentrico de farmacovigilancia de imunoterapia sublingual en pacientes alergicos. Allergol Immunopathol (Madr) 1995; 23: 153–61

  61. 61.

    Tinkelman DG, Cole WQ, Tunno J. Immunotherapy: a one-year prospective study to evaluate risk factors of systemic reactions. J Allergy Clin Immunol 1995; 95: 8–14

  62. 62.

    Lin MS, Tanner E, Lynn J, et al. Nonfatal systemic reactions induced by skin testing and immunotherapy. Ann Allergy 1993; 71: 557–62

  63. 63.

    Ostergaard PA, Kaad PH, Kristensen T. A prospective study on the safety of immunotherapy in children with severe asthma. Allergy 1986; 41: 588–93

  64. 64.

    Stewart GE, Lockey RF. Systemic reactions from allergen immunotherapy. J Allergy Clin Immunol 1992; 90: 567–78

  65. 65.

    Lockey RF, Nikoara-Kasti GL, Theodoropoulos DS, et al. Systemic reactions and fatalities associated with allergen immunotherapy. Ann Allergy Asthma Immunol 2001; 87(1 Suppl.): S46–55

  66. 66.

    Khinchi MS, Poulsen LK, Carat F, et al. Clinical efficacy of sublingual and subcutaneous birch pollen allergen specific immunotherapy: a randomized placebo controlled, double blind, double dummy study. Allergy 2004; 59: 33–44

  67. 67.

    Moller C, Dreborg S, Ferdousi HA, 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

  68. 68.

    Des Roches A, Paradis L, Menardo JL, et al. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract: VI. specific immunotherapy prevents the onset of new sensitizations in children. J Allergy Clin Immunol 1997; 99: 450–3

  69. 69.

    Marogna M, Spadolini I, Massolo A, et al. Randomized controlled open study with SLIT in real life: clinical efficacy and more. Allergy 2004; 59: 944–50

  70. 70.

    Novembre E, Galli E, Landi F, et al. Coseasonal sublingual immunotherapy reduces the development of asthma in children with allergic rhinoconjunctivitis. J Allergy Clin Immunol 2004; 114: 851–7

  71. 71.

    Passalacqua G, Bagnasco M, Mariani G, et al. Local immunotherapy: pharmacokinetics and efficacy. Allergy 1998; 53: 477–84

  72. 72.

    D’Amato G, Lobefalo G, Liccardi G, et al. A double blind placebo controlled trial of local nasal immunotherapy in allergic rhinitis to parietaria pollen. Clin Exp Allergy 1995; 25: 141–8

  73. 73.

    Lombardi C, Canonica GW, Passalacqua G. Sublingual immunotherapy is clinically safe in patients with oral allergy syndrome. Allergy 2000; 55: 677–8

  74. 74.

    Mempel M, Rakoski J, Ring J, et al. Severe anaphylaxis to kiwi fruit: immunologic changes related to successful sublingual allergen immunotherapy. J Allergy Clin Immunol 2003; 111: 1406–9

  75. 75.

    Marcucci F, Sensi L, Frati F, et al. Sublingual tryptase and ECP in children treated with grass pollen sublingual immunotherapy (SLIT): safety and immunologic implications. Allergy 2001; 56: 1091–5

  76. 76.

    Vervloet D, Birnbaum J, Laurent P, et al. Safety and clinical efficacy of rush sublingual cypress immunotherapy: preliminary results [abstract]. Allergy 2002; 57 Suppl. 73: 70

  77. 77.

    Grosclaude M, Bouillot P, Alt R, et al. Safety of various dosage regimens during induction of sublingual immunotherapy. Int Arch Allergy Immunol 2002; 129: 248–53

  78. 78.

    Bagnasco M, Mariani G, Passalacqua G, et al. Absorption and distribution kinetics of the mayor Parietaria allergen administered by noninjectable routes to healthy human beings. J Allergy Clin Immunol 1997; 100: 121–9

  79. 79.

    Bagnasco M, Passalacqua G, Villa G, et al. Pharmacokinetics of an allergen and a monomeric allergoid for oromucosal immunotherapy in allergic volunteers. Clin Exp Allergy 2001; 31: 54–60

  80. 80.

    Mailing HJ. Is sublingual immunotherapy clinically effective? Curr Opin Allergy Clin Immunol 2002; 2: 523–31

  81. 81.

    Wilson DR, Torres LI, Durham SR. Sublingual immunotherapy for allergic rhinitis (Cochrane review). Cochrane Database Syst Rev 2003; (2): CD002893

  82. 82.

    Di Rienzo V, Marcucci F, Puccinelli P, et al. Long lasting effect of sublingual immunotherapy in children with asthma due to house dust mites: a ten-year prospective study. Clin Exp Allergy 2003; 33: 206–10

  83. 83.

    Nelson HS. Advances in upper airway disease and allergen immunotherapy. J Allergy Clin Immunol 2003; 111: S793–8

  84. 84.

    Douglass J, O’Hehir R. Specific allergen immunotherapy: time for alternatives? Clin Exp Allergy 2002; 32: 1–3

  85. 85.

    Norman PS. Immunotherapy 1999–2004. J Allergy Clin Immunol 2004; 113: 1013–23

  86. 86.

    Bousquet J. Sublingual immunotherapy: from proven prevention to putative rapid relief of allergic symptoms. Allergy 2005; 60: 1–3

Download references

Acknowledgments

This article was partially supported by ARMIA (Associazione Ricerca Malattie Immunologiche e Allergiche). The authors have no conflicts of interest to disclose.

Author information

Correspondence to Dr Giorgio Walter Canonica.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Passalacqua, G., Guerra, L., Fumagalli, F. et al. Safety Profile of Sublingual Immunotherapy. Treat Respir Med 5, 225–234 (2006). https://doi.org/10.2165/00151829-200605040-00001

Download citation

Keywords

  • Rhinitis
  • Allergic Rhinitis
  • Urticaria
  • Grass Pollen
  • Systemic Adverse Event