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Oral and sublingual immunotherapy for allergic rhinitis
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2012. | This topic last updated: Nov 1, 2011.

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) has been of clinical interest because it offers 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.

The techniques, mechanisms of action, advantages, and limitations of OIT for allergic rhinitis will be reviewed here. 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 — Oral immunotherapy (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 (STIT) has been approved by the European regulatory authorities and is in use throughout the European Union (EU). In the United States, OIT has not been approved by the Food and Drug Administration at the time of this writing. In addition, there are no commercially available products specifically intended for OIT in the US, and no standardized information on how to prepare an oral extract from the available extracts intended for use in SCIT.

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 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 — Oral immunotherapy (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 suggests 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 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 oral immunotherapy. The following forms are most promising:

  • Sublingual aqueous extracts (SLIT) — 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. However, the data do not support a consistent benefit [19].
  • Sublingual tablets (STIT) — The 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 — The 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.

Types of allergens — The majority of studies of oral immunotherapy have been performed with pollen allergens in patients with allergic rhinitis. The use of food allergens or latex allergens in oral immunotherapy 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 SCIT. 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 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, STIT treatment for seasonal allergens is generally started two to three months prior to the start of the relevant pollen season. Continuous year-round OIT is another option, although this did not appear to be superior to preseasonal treatment after the first year, in one open label study of grass pollen SLIT [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 STIT 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, OIT is administered daily to weekly through the pollen season.

Duration of therapy — The optimal duration of a course of oral immunotherapy 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 — A 2011 systematic review of 60 randomized trials (published through 2009) included approximately 2300 adults and children receiving active SLIT treatment and equivalent numbers receiving placebo [25]. Most studies involved treatment with single pollens (most commonly grass) or house dust mite preparations, at a range of doses. 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)]. 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.

STIT (sublingual tablets) — Among the different approaches to oral immunotherapy, studies using sublingual tablets (STIT) 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 oral immunotherapy.

Single grass allergen — European studies with Timothy grass STIT have demonstrated clinical benefit in grass allergic subjects [11,26].

  • 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 STIT.
  • In a subsequent trial by a different group, 634 adult patients with grass-induced seasonal allergic rhinoconjunctivitis were treated with once daily treatment with Timothy STIT (Grazax®) containing 15 mcg Phl p 5 or placebo [26]. 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 pruritis (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 STIT (Graxaz®; ALK/Schering-Plough), conducted in 2007, failed to demonstrate comparable clinical benefit in contrast to the European studies reviewed above [27]. 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 rhinoconjunctival 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 STIT were completed in 2009 [28,29]. 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 to placebo-treated groups, in children/adolescents and adults, respectively. Neither serious treatment-related adverse events nor anaphylaxis was reported.

Multiple grass allergens — There are a limited number of high-quality studies in which multiple allergens were given simultaneously in OIT.

A standardized 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 rhinoconjunctivity to three different doses: 100 Index of reactivity units (IR) (equivalent to 8.3 mcg or allergen, 300 IR (25 mcg), or 500 IR (42 mcg)) [30]. Treatment was initiated 16 weeks prior to the grass season, with an incremental step-up dosing of 100 IR over the first 5 days until the final dose was achieved, and continued through the grass season.

Therapy was well-tolerated. Adverse effects included mild to moderate oral pruritis and/or throat irritation. No serious or life-threatening adverse events attributable to active study medication were reported. The highest two doses yielded significant improvement in rhinoconjunctivitis total symptom scores, and in secondary endpoints of clinical efficacy, compared with placebo or the lowest dose [30].

Another similar study of 278 children and adolescents with rhinoconjunctivitis found that the 300 IR dose was well-tolerated and effective in this age group as well [31]. Dosing two and four months preseason, in addition to during the grass season, were similarly effective in a randomized trial of 633 adults [32].

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. OIT appears to be similar to subcutaneous immunotherapy in these respects.

The Timothy grass STIT trial discussed above [26] was extended in its double-blind, randomized, placebo-controlled fashion for an additional two years with a subsequent two-year follow-up [33]. 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 immunotherapy treatment 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 [23,34]. 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 [23,35]. This is the first controlled study demonstrating that oral immunotherapy, like subcutaneous injection immunotherapy, can provide benefit that persists after treatment is discontinued.

SLIT (sublingual aqueous extracts) — Another approach to the delivery of OIT involves glycerinated aqueous allergen extracts that are initially held under the tongue for two to three minutes and then swallowed. 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 [36]. These clinical studies used the commercially available standardized glycerinated extracts currently licensed for subcutaneous immunotherapy.

Ragweed — The most advanced clinical trials have been performed with ragweed in a series of studies conducted by Greer Laboratories Inc (Lenoir, NC) [37,38]. These clinical studies used the commercially available standardized glycerinated ragweed extract currently licensed for subcutaneous immunotherapy.

  • 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 [37]. A standardized 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.
  • A dose-dependent treatment effect was observed for both active treatment groups in rhinoconjunctivitis symptom scores, but this fell just short of statistical significance in the high-dose treatment group [37]. However, a statistically significant reduction in need for seasonal anti-allergy "rescue" medication was demonstrated with high-dose ragweed oral-sublingual immunotherapy. 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.
  • In 2008, a larger Phase III clinical trial was conducted in >400 adult subjects with a history of ragweed-induced seasonal allergic rhinoconjunctivitis with or without asthma. Although the study results are not yet in publication, a company-issued press release cited that this multicenter clinical trial failed to achieve its primary endpoint. The study data is being further analyzed to define criteria that will be used in the design of future studies with the sublingual compound.

House dust mite — SLIT 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:

  • 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/d or 70mcg Der f1 per day), low dose SLIT or placebo [39]. 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 to placebo.
  • A combination allergen SLIT study investigated the immunologic biomarkers associated with treatment of grass and dust mite allergic patients with both sublingual preparations [40]. 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).

Multiple different pollen allergens — It is not yet certain that multiple different allergens can be given simultaneously in OIT without impacting efficacy. 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 [41]. Threshold for titrated nasal challenge, skin prick tests, and serum-specific IgG4 levels were statistically-shifted in favor of active treatment with timothy extract. A modest positive trend was observed in clinical parameters in the multiple pollens group, which did not reach clinical significance. Thus, further studies are needed to determine whether multiple different types of allergens can be combined. (See 'Issues requiring further study' below.)

Microencapsulated OIT with ragweed — Microencapsulated preparations of allergens have also been studied, although results have been somewhat more mixed.

In a unpublished precursor trial, microencapsulated (ragweed) pollen extract (MRPE, standardized for units of Amb a 1) was studied in 607 ragweed-allergic patients [42]. 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 [42,43]. 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. Thus, microencapsulated products require further study before they can be applied clinically.

Use in pregnancy — Published data addressing the safety of OIT or 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 — A small number of trials have examined the safety and efficacy of OIT in patients with rhinoconjunctivitis and concomitant asthma [44,45]. These studies suggest that OIT can be safely administered to most patients with asthma, although it may not significantly improve asthma control.

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 [44]. 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 STIT 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 STIT. 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 [45].

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 [45].

In the grass tablet-treated group, the primary endpoints of median improvement of rhinoconjunctivitis symptom scores and medication scores were met [45]. 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.

COMPARISON OF OIT AND SCIT

Advantages and disadvantages of OIT — There are several potential advantages of OIT, compared with SCIT:

  • OIT is safer, with fewer local and systemic allergic reactions than SCIT. Serious systemic adverse events are uncommon to rare with OIT, although a small number have been reported [46-48].
  • OIT is more comfortable for patients, since allergens are ingested rather than injected.
  • OIT is more convenient for patients and clinicians, because therapy is self-administered by the patient at home.
  • Less time is required to achieve a therapeutic effect with OIT, since benefit can be observed within three to four months, compared with four to six months for most SCIT schedules.

The disadvantages of OIT include:

  • Benefit is reliant upon consistent patient self-administration. Patients who regularly miss doses may not have satisfactory results. (See 'Practical considerations' below.)
  • OIT 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 — Few trials have directly compared SLIT and SCIT, and a firm conclusion cannot be made based upon these limited data [49-51].

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 [52,53]:

  • 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 oral immunotherapy? 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 [54]. Thus, patient selection may be critical to outcome.

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 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 STIT) 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 — OIT might be a valuable initial therapy for young allergic children, as it should be better tolerated than injections. However, it is not known if OIT 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 OIT for SCIT.
  • The asthmatic patient — Further studies are needed to define the therapeutic efficacy of OIT in the asthmatic patient. In addition, more information is required about the safety of OIT in the home setting in patients who, by definition, are at greater risk of adverse systemic reactions and/or anaphylaxis.
  • The non-compliant 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 non-compliance 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.

SUMMARY AND RECOMMENDATIONS

  • 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. The best results have been obtained with dissolvable sublingual tablets and aqueous solutions of allergen. (See 'Introduction' above and 'Methods' above.)
  • The immunologic changes that result from oral allergen immunotherapy appear to be similar to those induced by injection immunotherapy. (See 'Mechanisms of action' above.)
  • Oral immunotherapy is in use in many areas of Europe for the treatment of allergic rhinoconjunctivitis, but has not yet been approved by the Food and Drug Administration for use in the United States. (See 'Availability' above.)
  • The efficacy and safety of OIT has been demonstrated in high quality randomized trials in both Europe and the United States, in both children and adults. (See 'Efficacy and safety' above.)
  • The small number of studies that have included patients with concomitant 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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