Sublingual immunotherapy: A comprehensive review

doi:10.1016/j.jaci.2006.02.040

Journal of Allergy and Clinical Immunology

Volume 117, Issue 5, May 2006, Pages 1021-1035

https://doi.org/10.1016/j.jaci.2006.02.040 Get rights and content

Sublingual immunotherapy (SLIT) has been used with increasing frequency in Europe and is viewed with increasing interest by allergists in the United States. To address this interest, a Joint Task Force of the American College of Allergy, Asthma and Immunology and the American Academy of Allergy, Asthma and Immunology's Immunotherapy and Allergy Diagnostic Committees reviewed the available literature on SLIT and prepared this report. The task force concluded that despite clear evidence that SLIT is an effective treatment, many questions remained unanswered, including effective dose, treatment schedules, and overall duration of treatment. Until these have been determined, an assessment of the cost/benefit ratio of the treatment cannot be made. SLIT does appear to be associated with few serious side effects, but it has not been administered in high-risk asthmatic patients, nor in the studies reviewed has it been administered as a mixture of non–cross-reacting allergens. Furthermore, there is currently no allergy extract approved for this use in the United States, nor is there a Current Procedural Terminology code for billing purposes. All of these factors should be given careful consideration by anyone contemplating initiating SLIT treatment for their allergic patients.

Section snippets

Sublingual swallow or spit?

SLIT can be delivered by means of 2 methods. With sublingual spit, the vaccine is kept under the tongue for a short period and then spat out. This method was used in some of the earlier studies, but the majority of the studies used the sublingual swallow method. In this method the vaccine is kept under the tongue for 1 to 2 minutes and then swallowed. All articles with either of these methods were reviewed, but articles that used the oral route without a sublingual phase were excluded.

In a

Allergen dosing

The efficacy of subcutaneous immunotherapy (SCIT), the standard to which SLIT is compared, is dependent on the dose and quality of the allergen105, 106, 107, 108 and the duration of administration.109, 110 One method that might offer a common denominator for comparing dosing is the content in mass units of 1 or more major allergens in the extract. Fifty-seven of the 104 SLIT studies reviewed provided doses in micrograms of major allergen. The rest reported doses only in in-house units,

Clinical efficacy

Sixty-four studies provided some information on the clinical efficacy of SLIT.16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 44, 45, 46, 47, 48, 49, 51, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85 However, most studies did not provide information about the degree of reduction in symptoms, medication scores, or both. Other measures of efficacy that were provided

Immunologic response

The immunologic responses examined in studies of SLIT include local effects at the site of administration, systemic antibody and cellular responses, end-organ inflammation, and sensitivity to both specific and nonspecific challenges. These changes are summarized in Table E5 in the Online Repository at www.jacionline.org. Additionally, sublingual therapy has been evaluated for its effect on progression of the atopic state, the development of new skin test reactivity, and the progression from

Nasal

No changes have been detected in spontaneously occurring nasal eosinophils after SLIT41, 81; however, there was a reduction in the increase in eosinophil counts after an allergen challenge in comparison with that seen in placebo-treated patients.²⁶ In a study using allergoid grass pollen, there was a significant increase in nasal ECP levels in the SLIT and placebo groups in the pollen season, with no statistically significant difference between groups. However, the placebo group had an increase

Mechanism of SLIT

It has long been known that oral administration of an allergen favors the development of tolerance. Current understanding is that regulatory T cells secreting TGF-β are involved in this type of tolerance. Administration of high-dose allergen immunotherapy by means of subcutaneous injection also induces the development of regulatory T cells, with evidence that the secretion of both IL-10 and TGF-β is important in the mechanism of tolerance.⁹³ Because many patients receiving SLIT show immunologic

Safety of SLIT

All studies, including retrospective DBPC and observational studies with and without an open control group, that provided any information on safety or tolerance were considered.^§

Adverse reaction frequency and allergen dose

In the 66 SLIT studies that provided safety information reviewed in this article, there did not appear to be a consistent relationship between the adverse reaction rate or severity and the administered dose. In an 18-month study of 58 asthmatic children with dust mite allergy treated with a maintenance dose of 1.2 μg of Der p 1 3 times a week (15.4 μg of Der p 1 CMD), there were 32 SRs in approximately 6933 administered doses (0.46% per dose); 17 of these were classified as dose related

Safety of SLIT in young children

There were 3 studies, 2 observational and 1 postmarketing survey, which were specifically designed to assess the safety of SLIT in young children.53, 97, 98 In the first study 33 children with intermittent (12 patients) or mild persistent (17 patients) asthma or persistent rhinitis (33 patients), aged 1 year and 11 months to 3 years and 10 months (mean, 3 years and 2 months), were treated with a monomeric allergoid (Lofarma, various allergens, 4 drops of 3000 AU/mL daily).⁵³ The mean follow-up

SLIT for latex allergy

One study investigating the tolerability of SLIT for the treatment of latex allergy in 26 patients reported 257 adverse reactions in 1044 doses (24.6% of doses), 223 (21.4%) of which were classified as local reactions and 38 (3.6%) as SRs.⁹⁴ The rate of adverse reactions during the induction phase (90/366, 24.59% per dose) was almost the same as that during the maintenance phase (167/678, 24.63% per dose). No treatment was required in 44.7% of SRs, antihistamines alone were required in 26.3%,

Safety of SCIT versus SLIT

Four studies provide some safety comparison of SLIT and SCIT. In a 12-month, double-blind, double-dummy study of 20 patients with grass allergy, minor side effects were reported in the SCIT group, but there were no systemic side effects in either group.⁸² In a 23-month study comparing SCIT (11 patients) with SLIT (12 patients) treatment with Alternaria tenius for 2 years, “no local or systemic side-effects” were reported in the SLIT group, but SRs (character not described) were reported in the

Economics

Of the 55 million patients with allergy in the United States, approximately 2 to 3 million receive allergy immunotherapy injections. SLIT might present an opportunity for broadening the use of immunotherapy by extending it to those patients who are not candidates for SCIT because they dislike injections, find the frequent visits to the physician's office inconvenient, or are concerned with its safety. Thus the disease-modifying benefits of immunotherapy could be extended to a greater portion of

Adherence

Another factor to consider before SLIT treatment is prescribed is how adherence will be monitored and the patient's likely adherence with this home-based treatment. Few of the studies reviewed provided information about treatment adherence. Only one multicenter observational study was specifically designed to provide a quantitative measure of SLIT adherence.⁹⁹ Eighty-six patients with allergic rhinitis, asthma, or both prescribed SLIT for a single relevant allergen (41 HDM and 45 pollens) were

SLIT summary

•
Many questions remain unanswered regarding SLIT, including effective dose and schedule, timing (ie, preseasonal and both preseasonal and coseasonal), mechanism, and safety in high-risk groups.
•
Until the optimal effective dose and dosing schedule is established, a cost/benefit analysis of SLIT cannot be made.
•
Currently there is no CPT code for SLIT.
•
One barrier to endorsement of SLIT is the absence of an FDA-approved product for SLIT.
•
Physicians prescribing SLIT should provide specific instructions

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L’ITA aux 5-graminées permet, en toute sécurité, la diminution des symptômes allergiques et l’amélioration de la charge thérapeutique et de la qualité de vie des patients.
Respiratory allergies to grass pollens are very widespread in the general population and the treatment is generally symptomatic which sometimes remains insufficient. Grass pollen allergen immunotherapy is currently the only etiological treatment of seasonal allergic rhinitis apart from allergenic eviction.
The aim was to study the effectiveness of sublingual ITA tablets with 5-grasses on allergic disease and describe the adverse effects after one year of treatment.
We conducted a prospective, descriptive and evaluative study including 40 patients suffering from grass pollen allergic rhinitis. A grass pollen sublingual allergen immunotherapy was received and patients were followed during a one-year treatment to study the efficacy and the safety profile.
The mean age was 30.9 ± 12.25 years. The sex ratio (M/F) was 0.48. Allergic conjunctivitis was associated in 70% and allergic asthma was associated in 48% of cases. Allergen immunotherapy side effects were mild, consisting of local side effects. No severe side effects were observed. A decrease in allergic rhinitis symptoms was observed in 83% with improvement in medication score in 65%. All patients noted a decrease in conjunctivitis symptoms with a total regression in 54% of cases. A better asthma control was noted in 33%. Among the 19 patients suffering from asthma, we could decrease the drug use in 63% of cases during the first year of treatment. An improvement of the quality of life was observed in 78% of cases. Allergen immunotherapy was significantly more efficient in allergic rhinitis and conjunctivitis with patients under 30 years old.
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Cell-penetrating albumin enhances the sublingual delivery of antigens through macropinocytosis
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Innovations in oral immunotherapy have greatly advanced the therapeutic control of allergies. However, these therapeutic effects suffer from the fact that the amount of antigen delivered to antigen-presenting cells is limited given the formulations that are currently available. We recently designed a cell-penetrating albumin and found that this modified albumin enters cells via the induction of macropinocytosis. Herein, we report on a novel system for delivering antigens based on cell-penetrating albumin-inducible macropinocytosis that allows larger amounts of antigens to be delivered to antigen-presenting cells. A treatment with cell-penetrating albumin significantly increased the permeability of ovalbumin (45 kDa) or dextran (2000 kDa) on monolayers derived from human oral squamous carcinoma cells. Flow cytometric analyses showed that the cell-penetrating albumin treatment resulted in a significant elevation in the amount of dextran that was delivered to two types of antigen-presenting cells. Finally, mice that had been sensitized by Japanese cedar pollen extract (JCPE) and cell-penetrating albumin showed a decline in the frequency of nose-rubbing against a subsequent intranasal administration of JCPE. These findings suggest that the sublingual administration of cell-penetrating albumin efficiently delivers antigens to antigen-presenting cells via the induction of macropinocytosis, resulting in an enhancement in the therapeutic effect of sublingual immunotherapy.
Systemic Allergic Reactions and Anaphylaxis Associated with Allergen Immunotherapy
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Allergen immunotherapy is indicated in severe rhinoconjunctivitis with/without mild asthma. Immunotherapy, unlike anti-allergic drugs, has the potential to provide long-term clinical benefits for years after its discontinuation. Whereas subcutaneous immunotherapy has been the gold standard, the sublingual route has emerged as an effective and safer alternative for self-administration. In mite-allergic asthma, house dust mite sublingual tablets have been shown to prevent asthma exacerbations. Knowledge of mechanisms of immunotherapy has informed novel approaches and enabled the discovery of biomarkers to monitor response to treatment. Hymenoptera venom immunotherapy is highly effective and can be lifesaving. Oral immunotherapy directed against peanut and other foods have shown successful desensitization, but no long-term tolerance and a high level of side effects and is not for routine clinical use.
Guidelines for the prescription of allergen immunotherapy and patient follow-up — Clinical questions and revision of the literature
2021, Revue Francaise d'Allergologie
L’immunothérapie allergénique (ITA) aux allergènes respiratoires est à ce jour le seul traitement curatif des allergies. Nous avons précédemment publié la liste des recommandations pour la pratique cliniques (RPC) nationales pour la prescription de l’ITA et le suivi du patient. Pour la réalisation de ce travail, un groupe de plus de 50 allergologues français a rédigé un texte exhaustif basé sur 50 questions cliniques pratiques pour les prescripteurs d’ITA. Ces questions ont été classées en 7 groupes, pour focaliser l’attention sur le choix du patient, les indications et modalité de prescription d’une ITA, les schémas thérapeutiques, les voies d’administration de l’ITA, son efficacité et sécurité, le choix de l’allergène, le suivi du patient et sur d’autres aspects pratiques sur lesquels les allergologues peuvent s’interroger lors de la prescription d’un tel traitement. Les réponses aux 50 questions sont basées sur les résultats des études publiées dans la littérature, et, en cas d’impossibilité à repérer des données solides, sur l’avis des experts. Le but principal de ce travail est de donner aux prescripteurs un tableau clair des données les plus récentes et de les guider dans le choix du traitement optimal pour leur patients allergiques, en tenant compte de l’utilité pratique des questions, qui incluent aussi un regard sur le contexte clinique actuel de pandémie à SARS-CoV-2.
Allergen immunotherapy (AIT) for respiratory allergens is the only curative treatment for allergies. We previously published the list of the French National Clinical Practice Guidelines for AIT prescription and patient's monitoring. To carry out this work, a group of more than 50 French allergists wrote an exhaustive text answering 50 clinical questions that meet the specific needs of AIT prescribers. These questions have been classified into 7 groups, to focus on patient's choice, the indications and modalities of AIT prescription, treatment regimens, the routes of administration of AIT, its efficacy and safety, the choice of the allergen, patients’ follow-up and on other practical aspects that allergists may wonder about when prescribing such treatment. Answers to the 50 questions are based on the results of studies published in the literature, and, if hard data could not be found, on experts’ advice. The main goal of this work is to provide prescribers a clear picture of the most recent data and to guide them in choosing the optimal treatment for their allergic patients, taking into account the practical questions, which also include a look to the current clinical context, due to the SARS-CoV-2 pandemic.
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Allergen-specific immunotherapy may be indicated in allergic rhino-conjunctivitis, allergic asthma and hymenoptera venom allergy. Immunotherapy has been shown to be effective in reducing symptoms and requirements for anti-allergic drugs. It remains to date the only causal treatment for allergic disease. The mechanism of immunotherapy entails redirection of the T-lymphocyte response from a helper T cell type 2 phenotype in favor of a helper T cell type 1 phenotype and the induction of regulatory T cells. Currently approved immunotherapy products are administered via the subcutaneous and sublingual routes. Advantages of subcutaneous therapy are a broad spectrum of indications. Disadvantages are potential systemic allergic reactions and frequent doctor visits. Sublingual immunotherapy has been shown to result in fewer systemic allergic but more local reactions and may be more convenient.

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^∗This report was developed by a Joint Task Force of the Immunotherapy Committees of the American Academy of Allergy, Asthma and Immunology and the American College of Allergy, Asthma and Immunology.

Disclosure of potential conflict of interest: L. Cox is on the advisory board for Greer, Genentech/Novartis, and Clinical Therapeutics Local Respiratory and is on the speakers' bureau for GlaxoSmithKline, Pfizer, and AstraZeneca. D. Linnemann has consultant arrangements with MSD, Schering Plough, and Glaxo and is on the speakers' bureau for MSD, Schering Plough, Almirall, and Boehringer-Ingelheim. D. Weldon is on the speakers' bureau for GlaxoSmithKline and Sanofi-Aventis and is honoraria for AstraZeneca. The rest of the authors have declared that they have no conflict of interest.

Reprint requests: Lauri Sweetman, American Academy of Allergy, Asthma and Immunology, 611 E Wells St, Milwaukee, WI 53203. E-mail: [email protected].

View full text

Mechanisms of asthma and allergic inflammationSublingual immunotherapy: A comprehensive review

Section snippets

Sublingual swallow or spit?

Allergen dosing

Clinical efficacy

Immunologic response

Nasal

Mechanism of SLIT

Safety of SLIT

Adverse reaction frequency and allergen dose

Safety of SLIT in young children

SLIT for latex allergy

Safety of SCIT versus SLIT

Economics

Adherence

SLIT summary

Immunol Allergy Clin North Am

J Allergy Clin Immunol

Allergol Immunopathol (Madr)

Ann Allergy Asthma Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Allergol Immunopathol (Madr)

J Allergy Clin Immunol

J Allergy Clin Immunol

Lancet

Allergol Immunopathol (Madr)

Allergol Immunopathol (Madr)

Ann Allergy Asthma Immunol

J Allergy Clin Immunol

Allergol Immunopathol (Madr)

Allergol Immunopathol (Madr)

J Allergy Clin Immunol

J Allergy Clin Immunol

Ann Allergy Asthma Immunol

Allergol Immunopathol (Madr)

Ann Allergy Asthma Immunol

J Allergy Clin Immunol

Safety of sublingual-swallow immunotherapy in children and adults

Int Arch Allergy Immunol

Noninjection routes for immunotherapy

J Allergy Clin Immunol

Efficacy of sublingual allergen vaccination for respiratory vaccination for respiratory allergy in children. Conclusions from one meta-analysis

J Investig Allergol Clin Immunol

Efficacy and safety of sublingual immunotherapy

Ann Allergy Asthma Immunol

Safety of allergen-specific sublingual immunotherapy and nasal immunotherapy

Chem Immunol Allergy

A short assessment of sublingual immunotherapy

Int Arch Allergy Immunol

Consensus statement on the treatment of allergic rhinitis

Allergy

Sublingual immunotherapy for allergic rhinitis [review]

The Cochrane Collaboration

Is sublingual immunotherapy clinically effective?

Curr Opin Allergy Clin Immunol

Comparison of the clinical efficacy if subcutaneous and safety of subcutaneous and sublingual immunotherapy: methodological approaches and experimental results

Curr Opin Allergy Clin Immunol

The safety of sublingual-swallow immunotherapy: analysis of published studies

Clin Exp Allergy

Sublingual immunotherapy in pediatric patients: beyond clinical efficacy

Curr Opin Allergy Clin Immunol

Sublingual swallow or spit?

Allergy

Dose dependence of immunological response to sublingual immunotherapy

Allergy

Variation of the skin end-point in patients treated with sublingual specific immunotherapy

J Investig Allergol Clin Immunol

Efficacy of sublingual swallow immunotherapy in children with severe grass pollen allergic symptoms: a double-blind placebo-controlled study

Allergy

Double-blind, placebo-controlled clinical trial of preseasonal treatment with allergenic extracts of Olea europaea pollen administered sublingually

J Investig Allergol Clin Immunol

Clinical efficacy of sublingual-swallow immunotherapy: a double-blind, placebo-controlled trial of a standardized five-grass-pollen extract in rhinitis

Allergy

Grass pollen sublingual immunotherapy for seasonal rhinoconjunctivitis: a randomized controlled trial

Clin Exp Allergy

Allergic rhinitis due to house dust mites: evaluation of the efficacy of specific sublingual immunotherapy

Allergy

Double-blind, placebo controlled evaluation of sublingual immunotherapy with standardized olive pollen extract in pediatric patients with allergic rhinoconjunctivitis and mild asthma due to olive pollen sensitization

Mechanisms of asthma and allergic inflammation
Sublingual immunotherapy: A comprehensive review