Sublingual and oral immunotherapy for allergic rhinitis

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2013. | This topic last updated: Oct 15, 2013.
INTRODUCTION — Allergen immunotherapy for the treatment of allergic respiratory diseases has traditionally been administered by subcutaneous injections. Subcutaneous immunotherapy (SCIT) has proven efficacy in allergic rhinitis and asthma, but it requires regular injections at a clinician’s office (typically over a period of three to five years) and carries the risk of potentially serious systemic allergic reactions in response to the treatment itself.

Oral immunotherapy (OIT) offers several specific advantages over injection immunotherapy. OIT is more easily administered, avoids cumbersome injections regimens, and carries a much lower risk of anaphylaxis compared with SCIT. This article will discuss the mechanisms of action, advantages, and limitations of OIT for allergic rhinitis. The most common methods of administering immunotherapy via an oral route: sublingual aqueous allergen extracts (SLIT-aqueous), sublingual allergen tablets (SLIT-tablets), and enteric or microencapsulated allergen will also be reviewed. SCIT is discussed separately. (See “Subcutaneous immunotherapy for allergic disease: Indications and efficacy” and “Subcutaneous immunotherapy for allergic disease: Therapeutic mechanisms”.)

OIT for the treatment of other allergic diseases is reviewed separately. (See “Future therapies for food allergy” and “Latex allergy: Management”, section on ‘Immunotherapy’.)

Background — OIT was first proposed as a method of treatment for allergic disease in the early 1900s. In the 1980s, properly designed clinical trials first demonstrated a dose-dependent therapeutic response with specific and well-characterized aeroallergens. In 2006, the World Health Organization recognized the cumulative evidence that OIT represented a viable alternative to SCIT and encouraged continued clinical investigation to characterize optimal techniques [1].

Availability — Sublingual tablet immunotherapy (SLIT-tablet) has been approved by the European regulatory authorities and is in use throughout the European Union (EU). Some SLIT-tablets are available in Canada. In the United States, OIT has not been approved by the US Food and Drug Administration at the time of this writing. However, there is increasing “off-label” use of aqueous allergen extracts for sublingual immunotherapy. (See ‘Sublingual aqueous allergen extracts’ below.)

MECHANISMS OF ACTION — The gut is the largest mucosal organ of the body and is exposed to numerous foreign proteins on a constant basis. The normal response of the gut immune system to nonpathogenic proteins is tolerance, a fact which forms the basis for the concept of oral immunization.

The gut immune system is comprised of various physical barriers, secretory IgA, the gut-associated lymphoid tissue (GALT), and lymphoid organs (mesenteric lymph nodes, spleen, and liver). Within the GALT, two areas of importance for antigen processing are the tonsils and adjacent ring of lymphoid tissue in the posterior pharynx, and the Peyer’s patches of the duodenum, jejunum, and small intestine. The GALT is essential for normal tolerance to most foreign proteins, as well as in the immunologic response to oral immunotherapy (OIT). The role of the GALT in the pathogenesis of food allergy is reviewed elsewhere. (See “Pathogenesis of food allergy”.)

Allergens used in OIT are usually intended for absorption either in the mouth or within the small intestine, as the conditions of the gastric environment (pH and other factors) destroy many allergenic proteins. Whether the immunologic response to allergens absorbed through the oral mucosa is different from that to allergens absorbed through the intestine is an area of ongoing investigation.

Allergen extracts given sublingually are primarily taken up by dendritic cells in the mucosa and presented to T cells in the draining lymph nodes. Likely mechanisms of action include activation of T regulatory cells and downregulation of mucosal mast cells [2]. Within the oral and sublingual mucosa, effector cells, such as mast cells, are less numerous [2]. This characteristic of the oral mucosa is believed to be an important factor in the lower rates of adverse systemic allergic reactions seen with OIT.
Allergenic proteins that reach the small intestine are processed through columnar mucosal cells and presented to T lymphocytes within Peyer’s patches [3]. Allergen processing within the GALT is discussed in greater detail separately. (See “Pathogenesis of food allergy”.)
Under normal conditions, local tolerance is believed to arise through stimulation of antigen-specific T-helper (Th) cells to increase immunoglobulin A (IgA) production with concomitant suppression of IgG and IgM production [4]. Systemic tolerance occurs as a result of a decline in T-helper mechanisms or stimulation of T-suppressor cells involved in IgE production. Mechanisms of oral tolerance are discussed in more detail separately. (See “Pathogenesis of food allergy”, section on ‘Factors influencing sensitization or tolerance’.)
Immunologic changes following OIT — OIT is less well-studied than subcutaneous immunotherapy (SCIT), although similar immunologic mechanisms appear to be involved [5]. The immunologic changes observed with SCIT are discussed in more detail elsewhere. (See “Subcutaneous immunotherapy for allergic disease: Therapeutic mechanisms”.)

The following changes in the humoral responses to allergens are seen with OIT [6-13]:

Increases in allergen-specific IgG4 [6-8,10]. Several studies now suggest that IgG4 production is under the control of IL-10.
Blunting of seasonal increases in allergen-specific IgE [8].
OIT also results in changes in the cellular response to allergens, including [14-18]:

Increases in CD8+ T cells and decreases in the CD4:CD8 T cell ratio [8].
Increases in interleukin (IL)-10 production and IL-12/interferon-gamma by peripheral blood monocytes [14,15]. As mentioned previously, IgG4 production may be regulated by IL-10, and SCIT has been shown to induce T regulatory cells to produce IL-10. IL-10 down regulates Th2-dependent inflammation and suppressed B cell isotype switching to IgE. (See “Pathogenesis of allergic rhinitis (rhinosinusitis)”.)
Decreases in IL-13 levels and serum eosinophil cationic protein (ECP)/eosinophil ratio. Serum eosinophilic cationic protein is an indicator of activated eosinophils, and reductions in the ECP/eosinophil ratio suggest that a smaller percentage of eosinophils are in an activated state as a result of successful IT. Furthermore, IL-13 changes are associated with airway remodeling and its reduction is also a positive marker of successful IT.
METHODS — Oral immunotherapy (OIT) can be administered in several ways. Technical variations include preparation of allergen, the types of allergens used, the doses involved, and schedules of administration.

Forms of oral allergen immunotherapy — Several allergen preparations have been studied in OIT. The following forms are most promising:

Sublingual aqueous allergen extracts (SLIT-aqueous) — An aqueous extract of allergen is generally held under the tongue for a specified period of time and then swallowed. The allergen is taken up through the rich vascular-lymphoid network of the mouth. Oral solutions that are held in the mouth for a period of time, but then spit out rather than swallowed, have also been evaluated in clinical trials.
Sublingual allergen tablets (SLIT-tablet) — Allergen is formulated into a rapidly-dissolving tablet that is held under the tongue for one to two minutes and then swallowed.
Enteric and microencapsulated preparations — Allergen is contained in an enteric coated bead, or polymer, which passes through the stomach intact and then dissolves in the small intestine. This approach is designed to protect the allergenic proteins from breakdown in the stomach, but allow a pH-dependent release in the small intestine for processing by the gut-associated lymphoid tissue (GALT).
All forms of OIT involve several minutes of contact between the allergen and a mucosal surface, either in the mouth or, after passing through the stomach is a protected form, in the small intestine. Protocols in which the allergen is simply put in the mouth and promptly swallowed were not found to be effective in early studies and not developed further.

Types of allergens — The majority of studies of OIT have been performed with pollen allergens in patients with allergic rhinitis. There are a smaller number of studies of dust mite immunotherapy. The use of food allergens or latex allergens in OIT is discussed separately. (See “Future therapies for food allergy” and “Latex allergy: Management”, section on ‘Immunotherapy’.)

Doses — The cumulative amount of allergen administered in the course of a year is generally 20 to 200 times greater with oral forms of immunotherapy compared with subcutaneous immunotherapy (SCIT) [19]. In some studies, the daily dose of allergenic protein in micrograms is equivalent to the dose given every two to four weeks in SCIT.

A range of allergen doses were evaluated in a dose-exploratory Phase I safety study of patients with seasonal allergic rhinoconjunctivitis treated with grass pollen sublingual tablets [20]. Eighty-four subjects were randomized to seven different Timothy grass tablet strengths: 25,000; 75,000; 100,000; 300,000; 500,000; 750,000; and 1 million SQ-T units. In this system, 100,000 SQ-T units was equivalent to ~ 20 mcg Phleum p 5, a dose similar to the effective maintenance dose for grass pollen SCIT. No serious or systemic adverse events were observed in the study, providing evidence that daily doses as high as 1 million SQ-T units (~200 mcg Phleum p 5) were well tolerated.
A similar safety study of the 5-grass standardized allergen tablet for sublingual immunotherapy was performed to establish a tolerated dose for subsequent trials [21]. Doses of 100 to 500 IR were evaluated for safety and tolerability in 30 grass-allergic adults over a 10 day treatment period. Through incorporation of a 5-day up-dosing regimen, high-dose treatment with 500 IR (~42 mcg Group 5 major allergens) could be reached without significant untoward adverse events. The majority of adverse events were mild to moderate with the most common being oral pruritus, throat irritation, and tongue swelling. No serious adverse events occurred.
The reason(s) that higher doses are needed have not been fully defined, although they may include loss of allergen through digestion, as well as the immunologic effects of high versus low levels of allergen exposure in the gut.

Schedules — Escalating doses are administered once daily, usually beginning a few months before the pollen season. As an example, SLIT-tablet treatment for seasonal allergens is generally started two to three months prior to the start of the relevant pollen season. Continuous year-round SLIT is another option, although in one open-label study of grass pollen SLIT, this did not appear to be superior to preseasonal treatment after the first year [22]. However, the best approach is not clear, since the studies that showed persistent benefit two years after completion of a three-year course of therapy used continuous year-round treatment, as described below [23]. (See ‘Persistence of therapeutic benefit’ below.)

Maintenance doses are reached by 3 to 12 weeks of treatment. During the maintenance phase, SLIT is administered daily to weekly through the pollen season.

Duration of therapy — The optimal duration of a course of OIT has not been defined. However, one controlled but nonrandomized study of 78 patients undergoing dust mite SLIT for three, four, or five years found that patients experienced persistent reduction in symptoms lasting seven, eight, and eight years, respectively [24]. Based on this, the authors suggested four years of therapy was a reasonable goal until more data are available. Other studies evaluating the persistence of benefit after stopping therapy are reviewed below. (See ‘Persistence of therapeutic benefit’ below.)

EFFICACY AND SAFETY — The efficacy and safety of sublingual immunotherapy (SLIT), using products designed for oral use, has been demonstrated in a number of properly designed European trials, for both children and adults with allergic rhinitis. Trials involving each of the main forms of SLIT are reviewed below.

In a 2011 systematic review of 60 randomized trials (published through 2009), which included approximately 2300 adults and children receiving active SLIT treatment, treatment resulted in a statistically significant reduction in symptoms [standardized mean difference of -0.42 (95% CI -0.69 to -0.15)] and in medication requirements [standardized mean difference of -0.43 (95% CI -0.63 to -0.23)] [25]. Most studies involved treatment with single pollens (most commonly grass) or house dust mite preparations, at a range of doses. Fifteen studies included only children, with results that were similar to those in adults. There was a trend for greater improvement with treatments lasting longer than one year. Local side effects (oral pruritus and swelling, throat irritation) and nausea were more common with active treatment, although systemic adverse effects (rhinitis or rhinoconjunctivitis) were equal in active treatment and placebo groups. No trial reported anaphylaxis or the need to administer epinephrine. Effects on quality of life could not be assessed because a variety of different measurements were used. Publication bias could not be excluded, as with any systematic review.

There have been efforts to standardize the outcome measures in trials of immunotherapy for respiratory allergy, use validated tools that can be compared across studies, and reach consensus about what degree of therapeutic benefit should be considered clinically meaningful [26-28].

Many study designs have now chosen the clinical outcome of “total combined score” (TCS) as the accepted evaluation tool to measure primary efficacy. However, no standardized scoring methodology has been adopted across the industry for quantification of symptoms and medication use.
In an attempt to define clinically meaningful improvement, the World Allergy Organization (WAO) has proposed that a 20 percent mean reduction in TCS compared with placebo be demonstrated [29]. The decision as to what represents a sufficient therapeutic effect must be tempered by the risk:benefit ratio of the therapeutic agent. Traditionally, the “bar” has been set somewhat higher for a treatment such as immunotherapy, where the risk:benefit ratio is perceived as being greater. It is not clear that the bar will be lowered for oral immunotherapy (OIT), even though the safety data with the SLIT-tablet studies is consistently showing rates of anaphylaxis that are lower than those observed with subcutaneous immunotherapy (SCIT). As of this time, the FDA has not yet published final guidelines on what is an acceptable clinical effect with this combined assessment tool. However, as larger numbers of patients undergo treatment with standardized allergens in properly designed clinical trials of sublingual immunotherapy, it is anticipated that new guidelines will be issued.
Sublingual allergen tablets — Among the different approaches to OIT, studies using sublingual tablets (SLIT-tablet) of grass pollen have yielded some of the best results. The following series of studies illustrates the steps required to define an effective approach for each type of OIT.

Single grass allergen — European studies with Timothy grass SLIT-tablet have demonstrated clinical benefit in grass allergic subjects [11,30].

A randomized trial was conducted in 2002 to 2003 in centers throughout Europe to evaluate three different strengths of a Timothy grass sublingual tablet (Graxaz; ALK), compared with placebo in treating 855 adults with grass pollen-induced rhinoconjunctivitis [11]. Subjects were randomized to one of three doses of the major Timothy allergen (Phleum p 5): 2500 SQ-T units (0.5 mcg of major allergen), 25,000 SQ-T units (5 mcg), or 75,000 SQ-T units (15 mcg). Treatment was initiated eight weeks prior to grass pollen season and continued daily throughout the season (mean duration of therapy was 18 weeks).

Ninety-two percent of participants completed the trial. There was a significant improvement in quality of life (QOL) compared with placebo [11]. Reductions were observed in rhinoconjunctivitis symptom scores (16 percent) and medication usage (28 percent), but these did not reach statistical significance. Benefits were greatest in the highest dose group (15 mcg Phleum p 5). This study defined an effective dose for subsequent clinical trials with Timothy SLIT-tablet.
In a subsequent trial by a different group, 634 adult patients with grass-induced seasonal allergic rhinoconjunctivitis were treated with once daily treatment with a Timothy SLIT-tablet (Grazax) containing 15 mcg Phl p 5 or placebo [30]. Treatment was initiated 16 weeks preseason and continued during the season, within a study design that incorporated a two year maintenance phase and a two year follow-up on continued therapy.

There were no serious or life-threatening adverse events, and <4 percent of patients withdrew. A fivefold higher adverse event rate probably- or possibly-related to drug was observed with active drug versus placebo, including oral pruritus (46 versus 4 percent), mouth edema (18 versus 1 percent), ear itch (42 versus 1 percent), and throat irritation (9 versus 1 percent) respectively.

Mean rhinoconjunctivitis symptom scores and medication scores (30 and 38 percent, respectively) improved significantly compared with placebo (figure 1). Additionally, there were significant increases in the number of well days (53 versus 44 percent) and improvements in quality of life in the treatment group.
When protocols similar to those used in these high quality European studies were attempted in the US, initial results were disappointing. This created some controversy about the use of existing forms of OIT within the US patient population.

The first American study of SLIT-tablet (Graxaz; ALK/Schering-Plough), conducted in 2007, failed to demonstrate comparable clinical benefit in contrast to the European studies reviewed above [31]. A measurable clinical effect could not be observed, probably because the majority of patients in both the active and placebo arms failed to demonstrate an increase in rhinoconjunctivitis symptoms during the grass pollen season. Proposed explanations for this included low pollen counts during the years studied, and the influence of confounding allergens (eg, Johnson, Sweet Vernal, and/or Bermuda grass). In addition, overlapping pollen seasons may have been an important confounder in some US centers, as tree season in late April to early May can overlap with grass season in certain years, so that patients were significantly symptomatic at the start of the study from tree pollen and did not show meaningful changes resulting from treatment of grass pollen allergy. In Europe, allergenic tree species tend to be more limited in number.
A subsequent pair of US studies addressed these problems in study design and patient selection and was able to circumvent the geographic and weather-related vagaries of pollen seasons, as well as the negative influences of confounding allergens.

The first US randomized trials to demonstrate positive clinical outcomes with grass pollen SLIT-tablet were completed in 2009 [32,33]. The protocol was similar to the European studies and used a dose of 15 µg Phl p 5 in both adults and children. Both trials were large (300 to 400 patients each), and 85 to 90 percent of patients were sensitized to multiple allergens in addition to grass pollen. The primary endpoint, the combined daily symptom plus medication score, improved 26 and 20 percent compared with placebo-treated groups, in children/adolescents and adults, respectively. Neither serious treatment-related adverse events nor anaphylaxis was reported.
Multiple grass allergens — There is a small number of high-quality studies in which multiple allergens were given simultaneously in SLIT-tablet form.

A standardized five-grass pollen sublingual tablet has been produced (Oralair, Stallergenes) that contains allergens from five grass species that are prevalent in Europe: Timothy (Phleum), Rye (Lolium), June (Poa), Orchard (Dactylis), and Sweet Vernal (Anthoxanthum). A study to establish dosing of the 5-grass product randomized 628 grass-allergic adults with rhinoconjunctivitis to three different doses: 100 Index of Reactivity units (IR) (~8.3 mcg group five major grass allergen), 300 IR (~25 mcg), or 500 IR (~42 mcg) [34]. Treatment was initiated 16 weeks prior to the grass season, with an incremental step-up dosing of 100 IR over the first five days until the final dose was achieved, and continued through the grass season. Therapy was well-tolerated. Adverse effects included mild to moderate oral pruritus and/or throat irritation.

A statistically significant benefit was seen in the primary efficacy variable (rhinoconjunctivitis total symptom score) for both the 300 IR and the 500 IR treatment arms versus placebo (37 percent and 35 percent respectively), but not in the lower 100 IR dose arm [34]. Reliance on “rescue” medication was also significantly less in the active treatment groups. Improvements were observed for rhinoconjunctivitis quality of life and individual rhinitis symptom scores.
Another similar study of 278 children and adolescents with rhinoconjunctivitis found that the 300 IR dose was well-tolerated and effective in this younger age group [35]. Dosing two and four months preseason, in addition to during the grass season, were similarly effective in a randomized trial of 633 adults, treated for three consecutive seasons [36]. The mean average adjusted symptom score was 36 and 35 percent lower during the third season, for the two and four month groups, respectively, compared with placebo.
Another randomized, placebo-controlled trial administered the five-grass pollen sublingual tablet, at the 300 IR dose (~25 mcg/mL group five major allergens) to an American study population (n = 473 adults), and reproduced the findings from the European study cited above [37]. Compared with those receiving placebo, active-treatment patients showed a 28 percent improvement in the primary efficacy measure of Total Combined Symptom + Medication Score. Similar improvements were observed in the secondary outcome measurements, including daily rhinitis total symptom score (23 percent), daily rhinitis rescue medication score (46 percent), overall rhinoconjunctivitis quality of life questionnaire score, and respective individual symptom scores (except nasal itch). Despite the fact that many patients in this study were highly grass-allergic, the most frequent AEs in this trial were again oral pruritus, throat itch, and nasopharyngitis; there were no anaphylactic events and no patients required epinephrine.

In this study, an interesting observation was made about the choice of patients for OIT. Inclusion was based upon clinical history and a positive skin test reactivity reaction to Timothy pollen (prick skin test wheal >5 mm versus control), although Timothy-specific serum IgE levels were also measured. Eleven percent of skin test-positive study subjects had undetectable Timothy grass-specific serum IgE (<0.1 kU/L). This subgroup of patients was essentially asymptomatic during the grass pollen season, and thus did not benefit from therapy, suggesting that the combination of skin test sensitivity and serum-specific IgE can identify a more appropriate population of study patients for inclusion in clinical trials of immunotherapy and for treatment.
Single ragweed allergen — Efficacy and safety have been demonstrated with a ragweed SLIT-tablet standardized on the basis of the major ragweed allergen, Amb a 1. In a multinational trial of 784 adults with allergic rhinitis caused by ragweed (with or without conjunctivitis or mild asthma), subjects were randomly assigned to placebo or to three different doses of ragweed SLIT-tablet (containing 1.5, 6, or 12 units of Amb a 1 protein, where 1 unit ≈ 1 mcg) [38]. Therapy was initiated four months preseason and continued for one year (for safety monitoring). The primary endpoint was total combined symptom/medication score (TCS) during peak ragweed season. The 6 and 12 unit tablets reduced TCS by 19 percent (-1.58 points, 95% CI -2.8 to -0.36) and 24 percent (-2.04 points, 95% CI -3.30 to –0.79), respectively, which was statistically significant compared with placebo. Similar findings were shown for the entire ragweed season (18 and 27 percent reduction, respectively). The 1.5 unit dose also reduced TCS, but not to a statistically significant degree. As discussed previously, the World Allergy Organization (WAO) has proposed that a 20 percent mean reduction in TCS compared with placebo be considered a clinically meaningful benefit. Therefore, this dose-ranging study demonstrated meaningful clinical benefit for the 12 unit tablet. No serious systemic allergic reactions, anaphylaxis, or asthma exacerbations were reported. Approximately one-half of subjects receiving the 6 and 12 unit tablets noted itching and swelling of the mouth, throat, or ears, mostly of mild to moderate severity and limited in duration.

Persistence of therapeutic benefit — Some preliminary data are available about the persistence of benefit with several years of therapy, as well as after treatment is stopped. SLIT appears to be similar to SCIT in these respects, as illustrated by the following studies [30,36,39,40]:

The Timothy grass SLIT-tablet trial discussed above [30] was extended in its double-blind, randomized, placebo-controlled fashion for an additional two years with a subsequent two-year follow-up [39]. Three-hundred-fifty-five (355) of the original 634 participants volunteered to participate in the double-blind, placebo-controlled extension arm of this long-term treatment phase of the study. Clinically, the significant improvements in mean rhinoconjunctivitis symptom scores and QOL persisted in the extension phase. In addition, there was a continued increase in IgG4 levels through the course of the two years of treatment in the grass allergen tablet-treated group, while the antibody levels did not change in the placebo-treated group.

The grass SLIT-tablet was well-tolerated and <1 percent of participants dropped out due to a serious adverse event. In contrast to the first year of study, during which 46 percent of grass-treated subjects (versus 4 percent of placebo) reported oral pruritus, only four events of oral pruritus were reported. Thus, the therapy was better tolerated over time.

Subsequent reports provided information about the same group of patients, who had received three years of active therapy (or placebo), and were reevaluated one and two years after discontinuing treatment [23,41]. The grass allergen-treated group demonstrated sustained reductions in rhinoconjunctivitis symptom scores and medication scores and improvements in quality of life at the end of the second year following treatment [23,42]. Other studies have demonstrated similar persistence of effect [40]. These studies demonstrate that OIT, like subcutaneous injection immunotherapy, can provide benefit that persists after treatment is discontinued.

Sublingual aqueous allergen extracts — Another approach to the delivery of SLIT involves glycerinated aqueous allergen extracts that are initially held under the tongue for two to three minutes and then swallowed (ie, SLIT-aqueous). This construct has gained acceptance in Europe and is being studied in US clinical trials. In the United States, phase I studies on safety and tolerability have been carried out with ragweed, grass, house dust mite, and cat glycerinated extracts [43].

A 2013 systematic review, which included 63 randomized controlled trials and 5131 subjects, was performed to determine if there was evidence that SLIT-aqueous, performed with products equivalent to those available in the US, was safe and effective for allergic asthma and rhinoconjunctivitis [44]. Studies were only included if the methods could be replicated using allergen extracts available in the US. A meta-analysis of efficacy could not be performed because of the heterogeneity among studies. Instead, the authors judged the quality of the evidence that SLIT-aqueous improved symptoms scores, need for medication, and quality of life for allergic asthma, rhinitis, and conjunctivitis. There were no reports of anaphylaxis, confirming that SLIT-aqueous is well tolerated. For allergic rhinitis and conjunctivitis, the quality of the evidence was deemed “moderate,” as defined in the GRADE guidelines [45]. The same analysis performed on studies of children found that the evidence that SLIT-aqueous improved asthma scores was of high quality, and the evidence that it improved allergic rhinitis and conjunctivitis scores was of moderate quality [46].

However, lack of standardized methods for conducting clinical trials, allergen selection (standardized versus nonstandardized allergens), allergen dose and duration of therapy, and lack of uniformity regarding what defines a clinically meaningful effect significantly limits what can be learned from this review. Furthermore, many of the studies included were smaller phase 1 or 2 studies intended to evaluate safety, clarify dose, or examine mechanisms of action. In several instances, the clinical trials did not achieve significance for their primary endpoint and were only able to show an effect for secondary endpoints or upon subgroup analyses. This type of evidence does not meet the more rigorous standards required by various regulatory bodies and task forces [26,29,47].

Additional important limitations noted by the authors, and which directly impact the ability of clinicians to create SLIT-aqueous treatment protocols with proven efficacy, included the following:

Conclusions about effective dose ranges could not be drawn because the dosing units used in European products and American products are not interchangeable.
The effectiveness of multiple-allergen immunotherapy was not clear, which is important because most patients receiving subcutaneous injection immunotherapy in the US are sensitized to multiple allergens and are treated with multiple allergens.
Many of the patients included had allergic rhinoconjunctivitis with mild intermittent asthma, rather than asthma requiring maintenance controller therapy. This is discussed more below. (See ‘Patients with concomitant asthma’ below.)
Thus, there are several fundamental issues with SLIT-aqueous that require further study before clinicians can be confident that SLIT-aqueous using currently available American products represents an effective alternative to SCIT [48]. Of primary importance is the question of effective dose.

It is our opinion that the only definitive way to evaluate newer forms of immunotherapy, including SLIT-aqueous, is to use products with doses defined in well-established units [eg, micrograms of major allergen or bioequivalent allergy units (BAU)]. A small number of studies have been performed on North American populations that meet this requirement [49-54]. These studies used the commercially available standardized glycerinated extracts currently licensed for SCIT. However, the data from these more rigorous studies do not demonstrate consistent or clinically meaningful benefit. It is clear that further work is required with standardized allergens, as well as with mixes of multiple allergens to determine effective dose, tolerability, and clinical evidence of effect.

Ragweed: The most advanced clinical trials have been performed with ragweed in a series of studies conducted by Greer Laboratories Inc (Lenoir, NC) [49,50]. These clinical studies used the commercially available standardized glycerinated ragweed extract currently licensed for SCIT.

A randomized dose-response clinical trial was conducted in 115 adult patients with a history of ragweed-induced seasonal allergic rhinoconjunctivitis with or without asthma [49]. In this study, a modest improvement in the primary endpoint – the total rhinoconjunctivitis symptom score for the entire pollen season – was observed with both active treatment arms (~15 percent); however, this was not statistically significant. The secondary endpoint of rescue medication usage did reach significance in the high-dose group during the peak season. A short ragweed pollen extract was used, which was standardized based on the major ragweed allergenic protein, Amb a 1 (where 1 unit = 1 mcg Amb a 1). Treatment was initiated 8 to 10 weeks prior to the ragweed season and continued through the ragweed season. An initial “rush-dose” escalation was conducted, during which subjects were up-dosed to receive either a medium dose of antigen (4.8 units Amb a 1), a high dose of antigen (48 units Amb a 1), or placebo administered once daily as a maintenance regimen through the course of the ragweed season. No serious adverse events were attributable to SLIT, although mucosal adverse events were reported at higher frequency rates in the two active treatment arms as opposed to placebo.
House dust mite: SLIT-aqueous with house dust mite allergen can induce the immunologic changes associated with clinical improvement. However, significant reductions in clinical symptom scores and medication use have not been clearly demonstrated [51,52,55]:
A study of 31 patients with dust mite induced allergic rhinitis, with or without mild intermittent asthma, randomized patients to one year of treatment with high dose SLIT (4200 AU/day or 70 mcg Der f1 per day), low dose SLIT or placebo [51]. A commercial preparation in 50 percent glycerinated saline (10,000 AU/mL) was self-administered daily in a dose-escalation protocol. After one year of therapy, high dose SLIT increased the bronchial threshold to allergen challenge and increased allergen-specific IgG4. However, there were no significant reductions in symptoms scores or medication use in either treatment group compared with placebo.
A study of 18 children with rhinitis (with or without conjunctivitis and without asthma), who were monosensitized to dust mite, compared higher dose SLIT with placebo [55]. After one year of treatment, active therapy was not superior to placebo in improving rhinitis symptoms or medication use, and ocular symptoms improved in both groups. Despite the minimal clinical impact, various immunomodulatory changes were observed in the active treatment group.
A combination allergen SLIT-aqueous study investigated the immunologic biomarkers associated with treatment of grass and dust mite allergic patients with both sublingual preparations [52]. The study demonstrated that treatment resulted in an increase in markers of tolerance (IL-10 and TGF-beta) with corresponding decreases in Th-2 inflammatory cytokines (IL-4/IL-13).
Microencapsulated OIT with ragweed — Microencapsulated preparations of allergens have also been studied, although results have been mixed. This form of OIT requires further study before it can be applied clinically.

In an unpublished precursor trial, microencapsulated (ragweed) pollen extract (MRPE, standardized for units of Amb a 1) was studied in 607 ragweed-allergic patients [56]. Patients received 40 units Amb a 1 per day, 40 units Amb a 1 per week, or placebo. Treatment started 8 to 12 weeks prior to ragweed season and continued up to 24 weeks. Subjects receiving the once-daily regimen for 10 weeks experienced a 36 percent improvement in the primary endpoint. The therapy was generally safe and well-tolerated, though the number and severity of gastrointestinal side effects was higher with the once-daily regimen.
A 2007 clinical trial was designed to establish an effective and safe dose for oral microencapsulated immunotherapy [56,57]. Active treatment (40 mcg Amb a 1 per day; started 10 to 24 weeks pre-ragweed season) resulted in a significant increase in ragweed-specific antibody, but no clinical improvement in allergy symptoms compared with placebo.
USE IN PREGNANCY — Published data addressing the safety of oral immunotherapy (OIT) or sublingual immunotherapy (SLIT) in pregnancy is lacking. However, reports of adverse outcomes or fetal harm have not emerged despite decades of use in various countries. European manufacturers suggest an approach similar to the one used for injection immunotherapy, ie, that treatment not be initiated in a pregnant patient, but if a woman becomes pregnant during treatment, therapy could be continued provided the patient has not had significant allergic reactions to therapy in the past.

PATIENTS WITH CONCOMITANT ASTHMA — Some trials have examined the safety and efficacy of oral immunotherapy (OIT) in patients with rhinoconjunctivitis and concomitant asthma and suggest that OIT is safe in many patients with milder asthma [51,58-64]. Information about patients with moderate persistent asthma or those requiring daily inhaled glucocorticoids is relatively limited, which may be important, as sublingual immunotherapy (SLIT) is self-administered at home and these patients are, by definition, at greater risk of adverse systemic reactions and/or anaphylaxis.

Representative randomized trials of SLIT in patients with asthma are reviewed below.

Adults — A randomized trial of 114 adult subjects (aged 18 to 65) with mild to moderate grass pollen-induced asthma and rhinoconjunctivitis, assigned subjects to treatment with 75,000 SQ-T (15 mcg Phleum p 5), Timothy grass allergen sublingual tablet (Grazax), or placebo [65]. The primary endpoints were average asthma symptom and medication scores during the grass pollen season.

During the grass season, asthma symptom and medication scores rose slightly in both active and placebo groups, but no discernible differences were observed between groups. Consistent with other trials with the SLIT-tablet construct, significant improvement in mean rhinoconjunctivitis symptom scores, medication scores, and well days (37, 41, and 54 percent respectively) was observed in the group receiving active SLIT-tablet. No serious adverse events were reported in the study and the number of adverse events linked to asthma was reported as similar between groups.

This clinical trial provided data on the safety of self-administration of the grass allergen tablet in asthmatic subjects and showed that allergen treatment did not impair asthma control, although there was no significant improvement in asthma symptoms either.

Children — A randomized trial of 253 children (5 to 16 years of age) with seasonal allergic rhinoconjunctivitis with or without asthma, demonstrated that the same Timothy grass sublingual tablet formulation (75,000 SQ-T units (15 mcg Phl p 5)) was safe and effective, and did appear to have a positive impact on asthma symptoms and medication use [66].

Treatment was initiated 8 to 23 weeks prior to the grass season and continued through the season. Ninety-two percent of children completed the trial. No serious adverse events were assessed as being treatment-related [66].

In the grass tablet-treated group, the primary endpoints of median improvement of rhinoconjunctivitis symptom scores and medication scores were met [66]. The active treatment also showed a significantly greater number of “well days” versus placebo treatment. During the study, 105 children (42 percent) reported asthma (5 percent severe, 48 percent moderate). Although only 23 percent used any asthma medications, a relative difference in median asthma symptom score was observed in the active treatment group versus placebo-treated children and use of asthma “relief” medication was nominally lower in the active treatment group.


Advantages and disadvantages of OIT — There are several potential advantages of oral immunotherapy (OIT), compared with subcutaneous immunotherapy (SCIT):

Sublingual immunotherapy (SLIT) is safer, with fewer local and systemic allergic reactions than SCIT. Serious systemic adverse events are uncommon to rare with SLIT, although a small number have been reported [67-69]. The European literature has provided extensive data on the safety of OIT [70,71]. Well-designed clinical trials in Europe and North America are providing important safety information on research subjects receiving the newer sublingual pollen tablet constructs [72]. SLIT is more comfortable for patients, since allergens are ingested rather than injected.
SLIT is more convenient for patients and clinicians, because therapy is self-administered by the patient at home.
The disadvantages of SLIT include:

Benefit is reliant upon consistent patient self-administration. Patients who regularly miss doses may not have satisfactory results. (See ‘Practical considerations’ below.)
SLIT agents will probably be approved in the US for self/home administration, and patient education will be required to ensure that it is carried out safely and effectively. As an example, patients will require education about how to resume therapy after missed doses. Post-marketing surveillance studies should be performed to identify the frequency and severity of untoward reactions/adverse events that may be observed at an increased rate in the “real-world” use of these products.
At present, there are no commercially available allergen preparations sold in the United States that have been FDA-approved for oral use. Thus, use of the extracts intended for SCIT constitutes an “off-label” application of the product, which is not generally reimbursed by third-party payers. This has lead to hesitancy on the part of the US medical community to embrace this therapy.
Comparative efficacy — One group compared various meta-analyses of SLIT (via sublingual extracts or tablets) and SCIT studies that measured changes in symptom scores and medication use in patients with allergic rhinitis due to grass pollen treated with grass pollen immunotherapy [73]. The analysis included 36 randomized controlled trials of over 3000 treated patients and a similar number of placebo-treated controls. To account for the methodologic variation among the studies, results were converted to standardized mean differences. Although indirect and limited by a very high degree of heterogeneity, this analysis showed greater overall benefit with SCIT compared with SLIT.

A small number of trials have directly compared SLIT and SCIT [19,74-81]. Three randomized trials involved head-to-head, double dummy protocols [19,74,75]. Although each study had methodologic issues and small numbers of patients, two of three found SCIT to be at least somewhat more effective than SLIT.

The earliest study included 20 adults monosensitized to grass (and without asthma) treated with SLIT-aqueous or SCIT, which found that both therapies resulted in reductions in symptoms and medication scores of at least 50 percent after one year of therapy; however, there was no placebo arm [74]. In contrast, immunologic measures of efficacy, such as allergen-specific IgG4, changed only in the group receiving SCIT.
A subsequent trial involved 58 birch-allergic adults (one-third with asthma) treated with either SLIT-aqueous or SCIT [19]. Some were also sensitized to other allergens. Rhinitis disease severity was significantly reduced in both treatment arms compared with placebo, although the two therapies were not statistically different from each other.
In a third trial, 30 children, all with both rhinitis and asthma and monosensitized to house dust mite, were randomized to SLIT-aqueous, SCIT, or placebo [75]. SCIT significantly reduced rhinitis and asthma symptoms and medication use. SLIT modestly reduced symptoms for both rhinitis and asthma, and medication use for rhinitis, but the changes with SLIT were not statistically significant compared with placebo. The doses given were also not quantified in terms of micrograms of allergen, so it was difficult to assess whether SLIT dosing was adequate.
Other reviews have identified a few additional studies, although these studies were not as rigorous as those described already and reached the same conclusion [82-84].

Issues requiring further study — Further research is needed in several areas, in addition to optimizing dosing and delivery systems. Incompletely answered questions include the following [26,72]:

Can oral forms of immunotherapy be used to alter disease progression or prevent the onset of other allergic diseases? No studies have yet addressed this question.
Which patients are the best candidates for OIT? Because SLIT is safe and convenient, proponents have hoped this therapy could be administered by primary care providers. However, the first published trial of grass pollen SLIT administered to children and adolescents in the primary care setting failed to show efficacy [85]. Thus, patient selection may be critical to outcome.
Studies are needed to define optimal doses and dosing schedules. Both SLIT [30,32-35,66,72] and SCIT [86-88] can produce clinical benefit within three to four months, although the optimal duration of SLIT has yet to be defined.
Practical considerations — The optimal way to incorporate OIT into clinical practice remains to be determined. The following types of patients raise specific questions about the best use of OIT.

The polysensitized allergic patient — The most compelling data for use of OIT is in the monosensitized pediatric or adult patient with seasonal allergic rhinoconjunctivitis with or without mild asthma. Nearly all the high-quality studies available have shown benefit in this context. However, the typical patient in North America is sensitized to multiple aeroallergens, both seasonally and perennially. At present, the few multiple allergen studies performed in the US have not shown clinical benefit. In one study, 54 grass-allergic patients were randomized to placebo, monotherapy with Timothy extract (19 mcg Phleum p 5 daily), or Timothy extract plus nine additional unstandardized pollen extracts [53]. A modest positive trend was observed in clinical parameters in the multiple pollens group, which did not reach clinical significance.

However, a post-hoc analysis of data from six randomized trials of grass pollen tablet immunotherapy, including 1871 adults and children, found no significant difference in the benefit reported by patients who were monosensitized to grass and those who were polysensitized to grass and other allergens during the grass pollen season [89]. This analysis does not address the question of whether SLIT with one allergen has any effect on patients’ symptoms from exposure to other allergens, a controversy that also applies to SCIT. (See “SCIT: Preparation of allergen extracts for therapeutic use”, section on ‘Multiple-allergen immunotherapy extracts’.)

In addition, until a full range of oral products has been produced, tested, and made commercially available, it is not clear that it would be practical or cost effective to combine OIT (eg, grass SLIT-tablet) with SCIT in a patient with multiple allergen sensitivities, as opposed to simply continuing SCIT to cover all the allergens relevant to that patient.
The pediatric patient — SLIT might be a valuable initial therapy for young allergic children, as it should be better tolerated than injections. However, it is not known if SLIT will prove to have the same potential to prevent the development of asthma that has been shown with SCIT. Until well-controlled clinical trials determine this, clinicians and parents may be unwilling to substitute SLIT for SCIT.
The noncompliant patient — OIT requires a commitment by the patient to long-term daily maintenance therapy, and compliance may be lower than that obtained in supervised clinical trials. Adherence data from studies with “controller” therapies for asthma have shown that, by six months from the time of prescription, up to 40 percent of patients are no longer compliant with their treatment.

Compliance may be important for safety, as well as efficacy. Long-term surveillance reporting will be needed to ascertain the risks associated with noncompliance as related to stopping-restarting therapy, the tendency for patients to overdose in an attempt to “catch up” if they have missed doses, or when patients have gaps in their treatment schedule and attempt to restart it, possibly at times when symptoms are most severe.

Oral immunotherapy (OIT) involves the application of allergen to the oral mucosa or sublingual tissues for a few minutes, after which the preparation is swallowed. (See ‘Introduction’ above.)
The immunologic changes that result from oral allergen immunotherapy with inhalant allergens appear to be similar to those induced by injection immunotherapy. (See ‘Mechanisms of action’ above.)
OIT is in use in many areas of Europe for the treatment of allergic rhinoconjunctivitis. In the United States, products specifically designed for oral use are not yet approved by the US Food and Drug Administration and are not available outside of clinical trials. (See ‘Availability’ above.)
Three forms of OIT with inhalant allergens are in development for use in the United States: sublingual aqueous allergen extracts (SLIT-aqueous), dissolvable sublingual tablets (SLIT-tablet), and enteric and microencapsulated preparations. The best results have been obtained with SLIT-tablet formulations. (See ‘Methods’ above.)
The efficacy and safety of sublingual immunotherapy (SLIT), using products designed for oral use, has been demonstrated in a number of properly designed European trials, for both children and adults with allergic rhinitis. In the United States, well-designed clinical trials have reproduced these finding for SLIT-tablet, but not yet for SLIT-aqueous. Despite this, aqueous extracts are being used “off-label” in the US for SLIT. (See ‘Efficacy and safety’ above.)
The small number of studies that have included patients with both allergic rhinitis and allergic asthma found that OIT was generally well-tolerated, although efficacy in reducing the symptoms of allergic asthma has not been conclusively demonstrated. (See ‘Patients with concomitant asthma’ above.)
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