Sublingual and oral immunotherapy

Sublingual immunotherapy (SLIT) is a viable alternative to the subcutaneous route for the treatment of respiratory allergy, whereas the pure oral route has been abandoned because of its lack of efficacy. The main distinctive feature of SLIT is its optimal safety profile, which has been demonstrated in adults and children. The indications for SLIT are similar to those for the subcutaneous route. A long-lasting effect has been demonstrated for the sublingual route, but data are needed to determine the optimal dose and the preventive effect in asthma.     

Allergen-Specific Sublingual Immunotherapy for Respiratory Allergy

Present knowledge regarding the clinical efficacy and safety of sublingual immunotherapy (SLIT) for the treatment of respiratory allergy is reviewed. Allergenspecific immunotherapy is presently considered a ‘biological response modifier’ for the treatment of respiratory allergy, to be used in association with drug therapy and allergen avoidance. Its value in the treatment of these conditions has been established in position papers from the World Health Organization and the European Academy of Allergology and Clinical Immunology. Immunotherapy is usually administered subcutaneously (SCIT), and with this route several severe adverse events and fatalities have been described. Therefore, in the last 15 years, novel and safer routes of administration (local routes) have been developed. SLIT, in particular, has been investigated in 18 randomised controlled clinical trials. SLIT’s clinical efficacy (improvement in symptoms and reduction in drug intake) in both asthma and rhinitis has been clearly assessed in 16 of these studies and for the most common allergens. SLIT’s safety profile, derived from the clinical trials and from post-marketing surveillance studies, was shown to be satisfactory in both adults and children. The most frequently reported adverse events are gastrointestinal complaints, which can be avoided through appropriate dosage adjustment. For these reasons, SLIT has been accepted as a viable alternative to SCIT in recent position papers. The main advantages of SLIT are its safety (no severe systemic adverse event has ever been described) and good patient acceptance, especially in children; in addition, SLIT is a self-administered treatment that can be carried out at home by the patient. In contrast to injection immunotherapy, knowledge of the mechanisms of action of SLIT is still developing, albeit rapidly, although interesting data about its pharmacokinetics in humans are available. Data are also required concerning the possible preventive and long-lasting effects. SLIT is a viable alternative to SCIT, with the same rationale and indications. It is intended to be used in association with proper pharmacological treatment, at the earliest stages of the disease, for optimal management of respiratory allergy.     

Sublingual immunotherapy in preschool children: an update

Allergen immunotherapy is a subject widely debated by allergists. Currently, there are controversial discussions focused on the sublingual route. Sublingual immunotherapy (SLIT) has so far been used in Europe, Asia and Australia for the treatment of allergic respiratory diseases. The minimum age to start specific immunotherapy with inhalant allergens in children has not been clearly established, and position papers discourage its use in children younger than 5 years of age. Nevertheless, it is known that SLIT efficacy is higher when SLIT is started at an earlier age. The aim of this review is to focus on studies in preschool children evaluating SLIT safety and efficacy, in order to improve this practice at an earlier age in childhood.     

Long-lasting effect of sublingual immunotherapy in children with asthma due to house dust mite: a 10-year prospective study

BACKGROUND: Subcutaneous immunotherapy for respiratory allergy has shown a long-lasting efficacy after its discontinuation, whereas this evidence is still lacking for sublingual immunotherapy, despite the fact that it is widely used. OBJECTIVE: We aimed to evaluate whether a long-lasting effect of SLIT occurs, in a prospective parallel group controlled study. METHODS: Sixty children (mean age 8.5 years) suffering from allergic asthma/rhinitis due to mites were subdivided into two matched groups: 35 underwent a 4- to 5-year course of SLIT with standardized extract and 25 received only drug therapy. The patients were evaluated at three time points (baseline, end of SLIT and 4 to 5 years after SLIT discontinuation) regarding presence of asthma, use of anti-asthma drugs, skin prick tests and specific IgE. RESULTS: We found that in the SLIT group there was a significant difference vs. baseline for the presence of asthma (P 相似文献   

Oral and Sublingual Immunotherapy for Treatment of IgE-Mediated Food Allergy

Development of active therapies for IgE-mediated food allergy is a critical action step toward alleviating the adverse medical, psychosocial, and economic burdens on affected patients and families. Significant progress has been observed specifically in the application of single-allergen oral and sublingual immunotherapy for treatment of IgE-mediated food allergy, with emphasis on milk, egg, and peanut as the primary allergens. Oral immunotherapy (OIT) has demonstrated efficacy in promoting immunomodulatory effects that lead to the clinical outcome of desensitization, defined as reduced reactivity while on active OIT, in the majority of treated individuals; however, achievement of sustained unresponsiveness following cessation of therapy has been observed in a smaller subset of treated subjects. The potential therapeutic benefits of OIT must be carefully considered in light of the significant potential for adverse events ranging from self-limited or easily treated oropharyngeal, respiratory or gastrointestinal symptoms, to persistent abdominal complaints that lead to cessation of therapy in an estimated 10–15% of treated individuals. To date, the majority of studies have focused on single-allergen OIT approaches; however, multi-allergen OIT has shown promise in initial trials and is the subject of ongoing investigation to address the complex needs of multi-food allergic individuals. Sublingual immunotherapy (SLIT) has been utilized for the treatment of food allergy and pollen-food allergy syndrome, demonstrating moderate efficacy, a favorable safety profile and variable tolerability, with oropharyngeal symptoms most commonly observed. Although studies directly comparing OIT and SLIT are limited, in general, the favorable safety profile associated with SLIT comes at the expense of reduced efficacy, while the more robust clinical effects observed with OIT come at the risk of potentially intolerable, treatment-limiting side effects. Future investigation to address specific knowledge gaps including optimal dose, duration, age of initiation, maintenance schedule, mechanisms, predictors of risk and therapeutic response will be important to maximize efficacy, minimize risk and develop personalized, effective approaches to targeting food allergy.     

A bright future for sublingual immunotherapy--contra

Defining the role of sublingual immunotherapy (SLIT) for the treatment of allergic rhinoconjunctivitis and allergic asthma is hampered for various reasons: Heterogeneity in study designs, different allergen extracts and dosages, imperfect assessment strategies and partially inconclusive results. A number of questions need to be addressed before replacing subcutaneous immunotherapy (SCIT) by the sublingual route: Ideal dose, treatment duration, magnitude of improvement, modification of the immune response, long-term and preventive effects. At present, SLIT might be used in adults with pollen related rhinoconjunctivitis, particularly if SCIT is not suitable for the patient (i.e. systemic effects). Only few data support SLIT for house dust mite allergy or bronchial asthma. Due to a lack of convincing results SLIT for children should only be applied in controlled studies and not in the daily routine. A more substantiated and conclusive judgment of SLIT is possibly warranted in a few years, when more studies with larger patient groups have addressed open questions concerning SLIT.     

Pediatric sublingual immunotherapy efficacy: evidence analysis, 2009-2012

ObjectiveTo perform a structured analysis of the latest scientific evidence obtained for the clinical efficacy of sublingual immunotherapy (SLIT) in children.Data SourcesPubMed, Embase, reference lists from reviews, and personal databases were reviewed for original articles on clinical trials with SLIT in patients younger than 18 years published from January 1, 2009, through December 31, 2012, using broad search and medical subject heading terms.Study SelectionsClinical trials, irrespective of their design, of SLIT in the treatment of respiratory and food allergy in patients 18 years or younger were selected. Clinical outcomes (symptom scores, medication use, provocation tests, pulmonary function tests, skin prick tests, and adverse events) and immunologic changes were tabulated. Quality of each trial and total quality of compounded evidence was analyzed with the Grading of Recommendations Assessment, Development and Evaluation system.ResultsOf 56 articles, 29 met the inclusion criteria. New evidence is robust for the precoseasonal tablet and drop grass pollen SLIT efficacy in allergic rhinitis and scarce for seasonal asthma. Some evidence for Alternaria SLIT efficacy is appearing. For house dust mite (HDM) SLIT in asthma, there is high-quality evidence for medication reduction while maintaining symptom control; evidence for HDM SLIT efficacy in allergic rhinitis is of moderate-low quality. There is moderate evidence for efficacy of dual grass pollen–HDM SLIT after 12 months of treatment and 1 year after discontinuation. Specific provocation test results (nasal, skin) improve with grass pollen and HDM SLIT but nonspecific bronchial provocation testing does not. Food oral immunotherapy is more promising than food SLIT. Possible new surrogate markers have been reported. No anaphylaxis was found among 2469 treated children.ConclusionEvidence for efficacy of SLIT in children with respiratory or food allergy is growing.     

Noninjection routes for immunotherapy

Allergen specific immunotherapy, together with drugs and allergen avoidance, is a cornerstone in the management of respiratory allergy. The traditional subcutaneous route is burdened with the risk of severe adverse events; therefore, safer routes of administration (noninjection or local routes) have been investigated and developed. Controlled trials failed to demonstrate the clinical efficacy and the safety of oral and bronchial administration, and these routes have been abandoned. Local nasal immunotherapy proved effective and safe in 17 of 18 controlled trials; thus it is considered a viable route of immunotherapy. Nevertheless, nasal immunotherapy is effective in rhinitis only and requires a particular administration technique; therefore its use is slowly declining. The sublingual route is supported by numerous controlled trials showing its efficacy in asthma and rhinitis in adults and children. The safety profile, assessed in clinical trials and postmarketing surveillance studies, is satisfactory; the most frequent side effects are gastrointestinal complaints, which can be easily managed by proper dose adjusting. Sublingual immunotherapy is now accepted by the World Health Organization as a valid alternative to the subcutaneous route also in children. Although the long-lasting efficacy has been recently documented for the sublingual route, several points still need to be elucidated, including mechanisms of action, optimal dosage, cost-effectiveness, and adherence.     

Balancing efficacy against safety in sublingual immunotherapy with inhalant allergens: what is the best approach?

Over the last 20 years, studies and clinical trials have demonstrated efficacy, safety and cost–effectiveness of sublingual immunotherapy (SLIT) for respiratory allergic diseases. Nevertheless, it seems to be mostly used as a second-line therapeutic option, and adherence to treatment is not always optimal. Selective literature research was done in Medline and PubMed, including guidelines, position papers and Cochrane meta-analyses concerning SLIT in adult patients. The most recent reviews confirm SLIT as viable and efficacious treatment especially for allergic rhinitis, even if the optimal dosage, duration, schedule are not clearly established for most of the products. Despite an optimal safety profile, tolerability and patient-reported outcomes concerning SLIT have received poor attention until now. Recently, new tools have been specifically developed in order to investigate these aspects. Regular assessment of tolerability profile and SLIT-related patient-reported outcomes will allow balancing efficacy with tolerability and all the other patient-related variables that may affect treatment effectiveness beyond its efficacy.     

Sublingual immunotherapy for allergic rhinoconjunctivitis--the seeming and the real

BACKGROUND: Subcutaneous specific immunotherapy (SIT) has been shown to be a causal treatment with long-term efficacy for allergic rhinoconjunctivitis and asthma, and a preventive measure against the development of asthma and new sensitizations. As it is associated with several inconveniences and serious side effects, sublingual immunotherapy (SLIT) has been developed to evade these problems. METHODS: The present review of previously published studies on allergic rhinoconjunctivitis aimed to determine the efficacy of SLIT in comparison with subcutaneous treatment and to summarize long-term results of immunotherapy and its effects on the prevention and treatment of asthma and the prevention of new sensitizations. RESULTS: The effect of SLIT on allergic rhinoconjunctivitis is low to moderate, depends on the allergen used and is more pronounced in adults than in children, in whom a consistent effect has not been demonstrated. Direct comparison with SIT shows conflicting and inconsistent results. Detailed studies on the prevention of asthma and new sensitizations are not available. Consistent effects of asthma treatment on both symptom and medication scores and lung function have not been reported. A quantitative evaluation is not possible due to indistinct inclusion criteria and different outcome criteria. In summary, currently SLIT plays no significant role in the treatment of asthma, apart from children monosensitized to house dust mites in whom it may have low-moderate effects. Only one study deals with the long-term efficacy of SLIT, which demonstrated a persistent positive effect on asthma, whereas data on rhinoconjunctivitis are completely lacking. CONCLUSIONS: Primary and secondary targets of specific immunotherapy have not been answered satisfactorily for the sublingual route. To date, SLIT cannot be recommended as an adequate alternative to the subcutaneous form. Questions regarding the cumulative dose, duration of therapy and immunological mechanisms have also not been answered. The indication should thus be limited to adult patients with pollen-induced rhinoconjunctivitis being unable to perform SIT, e.g. due to significant side effects.     

Sublingual immunotherapy in pediatric patients: beyond clinical efficacy

PURPOSE OF REVIEW: Sublingual immunotherapy (SLIT) is widely used in several European countries. Many clinical trials and a meta-analysis presently support its efficacy, but limits and indications in pediatric age still need to be clarified. We review here the most recent literature on SLIT, with particular attention paid to the safety of children and to the additional clinical effects. RECENT FINDINGS: In addition to clinical trials, post-marketing surveillance studies have confirmed the optimal safety profile of SLIT in adults and children, including those below the age of 5 years. The most recent studies have shown that SLIT, identically to the subcutaneous route, has the potential to affect the immunological response to allergens. This is testified to by the facts that SLIT can prevent the onset of new sensitizations and maintain its beneficial effect for years after discontinuation. Moreover, it has been shown that SLIT can prevent the onset of asthma in children with rhinitis. SUMMARY: Due to its excellent safety, SLIT would be an optimal candidate for use in pediatric age groups, where the natural history of allergy can be to some extent modified. Nonetheless, formal and rigorous studies are needed to define its exact indication and dosage.     

Clinical efficacy and safety of sublingual immunotherapy with tree pollen extract in children

BACKGROUND: Subcutaneous immunotherapy has been the principal approach of immunotherapy in the treatment of allergic diseases. Several clinical studies with birch, alder or hazel pollen extract conducted as subcutaneous immunotherapy have been published suggesting a well-tolerated and clinically effective treatment. Only a few clinical studies of sublingual immunotherapy (SLIT) with these allergens have been published. This study investigated the clinical efficacy, safety and dose-response relationship of SLIT in children suffering from rhinoconjunctivitis with/without asthma. METHODS: Eighty-eight children (5-15 years) with a history of tree pollen-induced allergic rhinoconjunctivitis with/without seasonal asthma for >or=2 years were included. Allergy to tree pollen was confirmed by positive skin-prick test, positive specific IgE and positive conjunctival provocation test. The extract used was a glycerinated mixture of Betula verrucosa, Corylus avellana and Alnus glutinosa 100,000 SQ-U/ml. Children were randomized into three groups receiving SLIT 5 days a week for up to 18 months; dose group 1: accumulated weekly dose of 24,000 SQ-U; dose group 2: accumulated weekly dose of 200,000 SQ-U; and placebo. RESULTS: In the birch pollen season, dose group 2 showed a significant reduction of symptom (P = 0.01) and medication scores (P = 0.04) compared with placebo. Dose group 1 showed a significant reduction of symptom scores (P = 0.03). There were no statistical differences between dose groups 1 and 2. All children tolerated the treatment well. CONCLUSION: SLIT with tree pollen extract provided dose-dependent benefits in tree pollen-allergic children in terms of significantly reduced symptoms and medication use. The treatment was well tolerated.     

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

BACKGROUND: As the main target of sublingual immunotherapy (SLIT) is to reduce at most the occurrence of adverse events (AE), safety represents a critical issue. This aspect deserves particular mention when a higher dose of allergen extract than traditional subcutaneous immunotherapy (SCIT) is required to be effective: that may be up to 500 times that employed for SCIT. OBJECTIVE: All published controlled studies concerning SLIT-swallow were analysed to evaluate AE rates. METHODS: Studies were subdivided in two groups: (i) studies using low allergen dose (LAD), i.e. ranging from 1 to 50 times the dose commonly administered with SCIT, and (ii) studies with high allergen dose (HAD), i.e. ranging from 50 to 500 times the dose administered with SCIT. RESULTS: Twenty-five studies were altogether analysed: 13 studies belonged to the low-dose group, 12 belonged to the high-dose group. We considered all patients with at least one AE. Local reactions were significantly more frequent in the LAD group than in the HAD group (P<0.0001), while there was no difference in the rate of systemic reactions. Severe systemic reactions were never reported. CONCLUSION: This study represents the first analysis of the safety of SLIT concerning the allergen dose employed in the treatment. There is evidence that AE occurrence is substantially not dose-dependent. This fact highlights two main clinical aspects: the elevated tolerability of SLIT in general and the safety of HAD regimen.     

Sublingual allergen immunotherapy for respiratory allergies: what is new?

Sublingual immunotherapy (SLIT) is a disease-modifying treatment for respiratory allergies that has been used for many years in Europe and has also recently been approved for use in North America. Its use is thus likely to increase. There is more evidence available regarding SLIT efficacy and its good safety profile, making it an appealing treatment option. The majority of studies have mostly focused on grass pollens; however, there are now data available regarding efficacy for other allergens. This review will summarize recent findings from SLIT clinical trials for respiratory allergies, including efficacy, safety, post-discontinuation effects and use in different age groups. Grass pollen, tree pollen, house dust mite and ragweed SLIT studies will be evaluated.     

Advances in upper airway diseases and allergen immunotherapy

The purpose of this review is to highlight recently published important articles on upper airway diseases and immunotherapy. We review articles on rhinitis, sinusitis, conjunctivitis, and immunotherapy. New insights into epidemiology, pathophysiology, diagnosis, and therapy are described for each of the above diseases. Regarding immunotherapy, we discuss numerous clinical trials on sublingual and subcutaneous immunotherapy, mechanisms of immunotherapy, safety, and use of modified allergens and biological agents for immunotherapy.     

Adult and pediatric clinical trials of sublingual immunotherapy in the USA

Specific allergen immunotherapy has been practiced for allergic rhinoconjunctivitis for over 100 years and is the only treatment option that is disease modifying. In the USA, immunotherapy is usually administered via subcutaneous injection; this is the only route with a US FDA-approved formulation. There is growing interest in developing US-standardized formulations for the sublingual route, but up until recently there have been few US trials. Most of the experience with sublingual immunotherapy (SLIT) comes from Europe, where it is widely used and there is a large body of literature supporting its use. The purpose of this review is to summarize recent adult and pediatric clinical trials of SLIT in the USA. Most of the trials are for inhalant allergies, but there is some early work on SLIT as a novel therapy for food allergies.     

Economic evaluation of sublingual immunotherapy vs symptomatic treatment in adults with pollen-induced respiratory allergy: the Sublingual Immunotherapy Pollen Allergy Italy (SPAI) study.

BACKGROUND: Few data are available on the pharmacoeconomic aspects of immunotherapy. OBJECTIVE: To evaluate, from the health care system and societal perspectives, the costs and consequences of sublingual immunotherapy (SLIT) added to pharmacotherapy compared with drugs alone for respiratory allergy. METHODS: This study compared costs, clinical outcomes, and cost-effectiveness ratios of 2 strategies in the management of allergic rhinitis and asthma, namely, SLIT associated with pharmacotherapy and pharmacotherapy alone (no SLIT). A decision tree was developed and populated with epidemiologic and resource utilization data concerning approximately 2,200 patients. Direct costs included visits, tests, pharmacotherapy, immunotherapy, and hospitalizations. Indirect costs and out-of-pocket drugs were also included. Outcome was calculated as the number of improved patients and asthma cases avoided at 6 years. Sensitivity analysis was performed by varying costs and epidemiologic data. RESULTS: SLIT improved the symptoms of 399 of 1,000 patients and prevented asthma in 229 of 1,000 patients compared with drugs alone. For SLIT added to pharmacotherapy and pharmacotherapy alone, the direct cost per patient at more than 6 years was Euro2,400 and Euro3,026, whereas the indirect cost was Euro1,913 and Euro3,400. CONCLUSION: From both perspectives and for both effectiveness end points, SLIT is less expensive and more effective than pharmacotherapy alone.     

A comparative analysis of symptom and medication scoring methods used in clinical trials of sublingual immunotherapy for seasonal allergic rhinitis

Symptom and medication use are the key outcomes for assessing the efficacy of subcutaneous (SCIT) and sublingual allergen immunotherapy (SLIT). Our objective was to explore the similarities and differences between existing scoring mechanisms used in clinical trials of SLIT for seasonal allergens and characterize the impact that such differences may have on efficacy reporting. Randomized, double‐blind, placebo‐controlled clinical trials investigating the efficacy of SLIT for seasonal allergic rhinitis (2009–2013) were selected for review. Simulated and published data were used to demonstrate differences in scoring methods. Symptom and medication scoring methods across trials, although all designed to achieve the same objective, included important differences. The maximum daily symptom score (DSS) can vary widely depending on the number of symptoms assessed, and terminology of symptoms is not consistent. Similarly, daily medication scoring (DMS) methods differ greatly among studies and are dependent on medications allowed and weighting of scores assigned to each medication. When published DSS and DMS scores were used to calculate simulated daily combined scores (DCSs) based on various published methods, changes from placebo ranged from 19% to 29% when assuming all variables other than the DSS and DMS methods were equal. Variations in trial design, analysis, and seasonal characteristics also have effects on symptom and medication scoring outcomes. We identified multiple differences in trial scoring methods and design that make comparison among trials difficult. Symptom, medication, or combined scores cannot be indirectly compared among trials without taking the methods of scoring and other trial differences into account.     

SQ house dust mite (HDM) SLIT-tablet provides clinical improvement in HDM-induced allergic rhinitis

House dust mite (HDM) allergy represents a highly prevalent inhalant allergy, and exposure to HDM allergens results in allergic rhinitis with persistent symptoms that may not be adequately controlled with available allergy pharmacotherapy. Allergy immunotherapy constitutes a complementary treatment option targeting the underlying immunological mechanisms of allergic disease and represents the only treatment with a potential for disease modification and long-term efficacy. As traditional allergy immunotherapy delivered by subcutaneous injection of specific HDM allergens involves a time-consuming treatment regimen and a risk of systemic adverse reactions, sublingually administered allergy immunotherapy (SLIT) has been investigated as a more convenient treatment option with similar levels of efficacy and an improved safety profile that allows for at-home daily administration.

In this Drug Profile, we provide a review of the clinical data behind the SQ HDM SLIT-tablet, which was recently approved for the treatment of HDM-induced allergic rhinitis by regulatory authorities in Europe and Japan.