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Disclosures: Peter S Creticos, MD Grant/Research/Clinical Trial Support: Merck (SLIT studies with allergens); Stallergenes (SLIT studies with allergens); Greer (SLIT studies with allergens); Circassia (Peptide IT with allergens). Consultant/Advisory Boards: Greer; Circassia (Allergen immunotherapy [Allergens for immunotherapy]). Philip S Norman, MD Nothing to disclose. Anna M Feldweg, MD Employee of UpToDate, Inc.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
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.
The alternate approach of administering allergens orally, and more specifically with a sublingual methodology in which the allergen is given as either a dissolvable tablet (under the tongue) or as an aqueous or liquid extract, has evolved into a viable treatment for allergic respiratory diseases. Sublingual immunotherapy (SLIT) offers several specific advantages over injection immunotherapy. SLIT can be self administered by patients or caregivers, does not require injections, and carries a much lower risk of anaphylaxis compared with SCIT. This article will discuss the mechanisms of action, advantages, and limitations of SLIT for allergic rhinitis, and the most common methods of administering immunotherapy via an oral route: sublingual allergen tablets (SLIT-tablets) and sublingual aqueous or glycerinated liquid preparations (SLIT-drops).
The use of SCIT for the treatment of allergic respiratory diseases is discussed separately. (See "Subcutaneous immunotherapy for allergic disease: Indications and efficacy" and "Subcutaneous immunotherapy for allergic disease: Therapeutic mechanisms" and "SCIT: Standard schedules, administration techniques, and monitoring".)
Oral immunotherapy for the treatment of other allergic diseases is reviewed elsewhere. (See "Future therapies for food allergy" and "Latex allergy: Management", section on 'Immunotherapy'.)
Background — Oral immunotherapy 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 1998, the World Health Organization recognized that SLIT was a promising alternate mode of immunotherapy and encouraged continued clinical investigation into this form of treatment . In 2009, the World Allergy Organization (WAO) published their opinion that the cumulative evidence showed SLIT represented a viable alternative to SCIT and encouraged continued clinical investigation to characterize optimal techniques [2,3].
SUBLINGUAL ALLERGEN IMMUNOTHERAPY — Several types of allergen preparations have been studied in sublingual immunotherapy (SLIT). The following forms are most promising:
●Sublingual allergen tablets (SLIT-tablets) – Allergen is formulated into a rapidly-dissolving tablet that is held under the tongue until completely dissolved. The majority of United States clinical studies have defined a single optimal dose based on prior dose-ranging safety studies. The tablets are self administered, once daily.
●Sublingual aqueous or glycerinated liquid allergen extracts (SLIT-drops) – An aqueous or liquid (eg, glycerinated) extract of allergen, generally administered as drops, is held under the tongue for a specified period of time and then the residual is 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, holding the extract under the tongue appears more efficient for delivery of active drug.
Other approaches to oral immunotherapy that have been investigated in research trials include administration of the allergen(s) as enteric-coated tablets, liposomal constructs, or microencapsulated polymers. These oral (swallow) delivery systems are intended to protect the allergenic proteins from breakdown in the stomach, and then allow a pH-dependent release in the small intestine for processing by the gut-associated lymphoid tissue (GALT). However, research studies with these constructs have not, as of yet, demonstrated evidence for effective delivery [4,5].
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 April 2014 the US Food and Drug Administration (FDA) announced approval of a five-grass sublingual tablet produced by Stallergenes (Oralair) , followed by a Timothy grass tablet produced by Merck (Grastek) . These are the first immunotherapy tablets to receive FDA approval in the United States. The Allergenic Products Advisory Committee (APAC) to the FDA has also recommended approval of a ragweed tablet product being developed by Merck. (See 'Sublingual tablets' below.)
In the United States, there has been "off-label" use of liquid allergen extracts for sublingual immunotherapy (SLIT). The issues regarding this practice are discussed below. (See 'Sublingual drops' 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 immunoglobulin A (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. The role of the GALT in the pathogenesis of food allergy is reviewed elsewhere. (See "Pathogenesis of food allergy".)
Allergens used in sublingual immunotherapy (SLIT) 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 . Within the oral and sublingual mucosa, effector cells, such as mast cells, are less numerous . This characteristic of the oral mucosa is believed to be an important factor in the lower rates of adverse systemic allergic reactions seen with SLIT.
●Allergenic proteins that reach the small intestine are processed through columnar mucosal cells and presented to T lymphocytes within Peyer's patches . 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 IgA production with concomitant suppression of IgG and immunoglobulin M (IgM) production . Systemic tolerance occurs as a result of a decline in T helper mechanisms or stimulation of T suppressor cells involved in immunoglobulin E (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 SLIT — SLIT is less well studied than subcutaneous immunotherapy (SCIT), although similar immunologic mechanisms appear to be involved . 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 SLIT [12-19]:
●Increases in allergen-specific immunoglobulin G4 (IgG4) [12-14,16]. Several studies now suggest that IgG4 production is under the control of interleukin-10 (IL-10).
●Blunting of seasonal increases in allergen-specific IgE .
SLIT also results in changes in the cellular response to allergens, including [20-24]:
●Increases in CD8+ T cells and decreases in the CD4:CD8 T cell ratio .
●Increases in IL-10 production and IL-12/interferon-gamma by peripheral blood monocytes [20,21]. 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 downregulates 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 ECP 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 immunotherapy. Furthermore, IL-13 changes are associated with airway remodeling and its reduction is also a positive marker of successful immunotherapy.
Types of allergens — The majority of studies of sublingual immunotherapy (SLIT) 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 oral immunotherapy is discussed separately. (See "Future therapies for food allergy" and "Latex allergy: Management", section on 'Immunotherapy'.)
Administration of specific products — For most products, therapy is initiated with a full dose, sometimes given under medical supervision, and then administration continues once daily and is self administered by the patient or caregiver at home.
●SLIT-tablets are held under the tongue until completely dissolved.
●SLIT-drops are held under the tongue for one to two minutes and then the residual is swallowed.
Five-grass sublingual tablet — The five-grass pollen sublingual tablet (Oralair, Stallergenes) is indicated for the treatment of grass pollen-induced allergic rhinitis with or without conjunctivitis in patients aged 10 to 65 years of age. Sensitization to any of the five grass species contained in the tablet (Timothy, Orchard, Perennial Rye, Kentucky Blue Grass, Sweet Vernal) should be confirmed by positive skin test or in vitro testing for pollen-specific immunoglobulin E (IgE) antibodies to any of the five grass species contained in the tablet.
The tablet is administered under the tongue and held there for at least one minute or until fully dissolved. The patient should be instructed not to ingest food or beverage for five minutes following dissolution of the tablet. The first dose is to be taken at the clinician's office under medical supervision, and patients should be observed for at least 30 minutes for signs of allergic reactions . Subsequent doses are to be administered once a day by the patient (or the patient's caregiver). Dosing is expressed in "index of reactivity" (IR) units. For children 10 to 17 years of age, a two-day dose escalation is stipulated (100 IR tablet on day 1, two 100 IR tablets on day 2, one 300 IR tablet daily thereafter, if tolerated). Patients 18 years and older start with the full 300 IR tablet, which contains approximately 25 mcg/mL of group 5 major allergens. Treatment should be started four months (16 weeks) prior to the expected onset of the respective grass season and continued through the grass season. The most common adverse effects were oral pruritus, throat irritation, ear pruritus, and mouth edema (25, 22, 8, and 8 percent, respectively).
The manufacturer of the product recommends that patients who are treated with Oralair should also be prescribed self-injectable epinephrine and instructed in its proper use. This product was not studied in patients with moderate or severe asthma or those requiring daily-controlled therapy. It is also recommended that patients with asthma do not take Oralair when they are experiencing an acute asthma exacerbation and that they be reassessed to determine if it is appropriate to continue therapy.
Timothy grass sublingual tablet — The Timothy grass pollen sublingual tablet (Grastek, Merck) contains 2800 bioequivalent allergy units (BAUs) of Timothy grass pollen (approximately 15 mcg Phl p 5) and is indicated for the treatment of grass pollen-induced allergic rhinitis, with or without conjunctivitis, in patients aged 5 to 65 years. Allergy to Timothy or to a cross-reactive grass species (sweet vernal, orchard/cocksfoot, perennial rye, Kentucky blue/June grass, meadow fescue, or redtop) should be confirmed by positive skin test or in vitro testing for pollen-specific immunoglobulin E (IgE) to Timothy grass or to one of the cross-reactive grass pollens.
The tablet is administered under the tongue and held there until fully dissolved, after which the patient should not ingest food or beverages for five minutes. The first dose is to be taken at the clinician's office under medical supervision, and patients should be observed for at least 30 minutes for signs of allergic reactions . Subsequent doses are to be administered once a day by the patient (or the patient's caregiver). Treatment should be started three months (12 weeks) prior to the expected onset of the respective grass season and continued through the grass season. It may be taken throughout the year and for three consecutive years, although the optimal schedule of treatment has not been determined.
The Timothy grass pollen sublingual tablet is labeled as "contraindicated in patients with severe, unstable, or uncontrolled asthma; a history of any severe systemic allergic reaction; a history of any severe local reaction after taking sublingual allergen immunotherapy; a history of eosinophilic esophagitis; or hypersensitivity to any of the inactive ingredients" (eg, fish-derived gelatin) . The most common adverse effects were oral pruritus, throat irritation, mouth edema, and ear pruritus (24, 21, 10, 7, respectively).
The manufacturer of the product recommends that patients should also be prescribed self-injectable epinephrine and instructed in its proper use. The product was not studied in patients with moderate or severe asthma or those requiring daily-controlled therapy. It is also recommended that patients with asthma do not take Grastek on days when they are experiencing an acute asthma exacerbation, and that they be reassessed to determine if it is appropriate to continue therapy.
It is also recommended that patients with asthma do not take Grastek on days when they are experiencing an acute exacerbation of their asthma, and in such a situation, a careful reassessment of the patient should be made to determine that continuation of treatment is appropriate.
Doses used in SLIT — The cumulative amount of allergen administered in the course of a year is generally 20 to 200 times greater with SLIT compared with subcutaneous immunotherapy (SCIT) . 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.
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 . 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 standardized-quality tablet (SQ-T) units. In this system, 100,000 SQ-T units was equivalent to approximately 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 one million SQ-T units (approximately 200 mcg Phleum p 5) were well tolerated.
●A similar safety study of the five-grass standardized allergen tablet for SLIT was performed to establish a tolerated dose for subsequent trials . 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 five-day up-dosing regimen, high-dose treatment with 500 IR (approximately 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.
Schedules — Treatment is typically initiated 12 to 16 weeks prior to the allergen season and maintained through the pollen season 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 . 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 . (See 'Persistence of therapeutic benefit' below.)
Duration of therapy — The optimal duration of a course of SLIT 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 . 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.)
SPECIFIC STUDIES AND EFFICACY DATA — 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]) . 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, to use validated tools that can be compared across studies, and to reach consensus about what degree of therapeutic benefit should be considered clinically meaningful [3,34,35].
●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 . 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, 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 US Food and Drug Administration (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 SLIT, it is anticipated that new guidelines will be issued.
Sublingual tablets — Among the different approaches to oral immunotherapy, studies using sublingual tablets (SLIT-tablets) of grass pollen extract 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 SLIT.
Single grass allergen tablet — European studies with Timothy grass SLIT-tablet have demonstrated clinical benefit in grass-allergic subjects [17,37].
●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 . Subjects were randomized to one of three doses of the major Timothy allergen (Phleum p 5): 2500 standardized-quality tablet (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 compared with placebo . 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 Phleum p 5 or placebo . Treatment was initiated 16 weeks preseason and continued during the season, within a study design that was extended to incorporate a two-year maintenance phase and a two-year follow-up on postdiscontinuation of therapy. (See 'Persistence of therapeutic benefit' below.)
In this initial study, 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. 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 United States, initial results were disappointing. This created some controversy about the use of existing forms of SLIT within the United States patient population.
The first American study of the Timothy grass SLIT-tablet (Merck), conducted in 2007, failed to demonstrate comparable clinical benefit in contrast to the European studies reviewed above . 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 United States 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.
●Subsequent United States studies addressed these problems in study design and patient selection and were able to circumvent the geographic- and weather-related vagaries of pollen seasons, as well as the negative influences of confounding allergens.
The first United States randomized trials to demonstrate positive clinical outcomes with this Timothy grass pollen SLIT-tablet were completed in 2009 [39,40]. The protocol was similar to the European studies and used a dose of 15 mcg Phleum 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 (was reduced) by 20 percent (difference versus placebo -1.31 [95% CI -2.8 to -0.36]) in adults and 26 percent (difference versus placebo -1.63 [95% CI -2.60 to -0.66]) in adolescents and children .
A 2014 United States SLIT study with the Timothy grass tablet showed efficacy in both primary and secondary outcomes, and provided further assurance on safety, as it evaluated 1501 grass-allergic children and adults, the largest published trial of immunotherapy . Efficacy was similar to that demonstrated in the positive trials performed earlier [39,40].
Multiple grass allergen tablet — There are a number of high-quality studies with the five-grass pollen tablet [42-47]:
●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 five-grass product randomized 628 grass-allergic adults with rhinoconjunctivitis to three different doses: 100 index of reactivity (IR) units (approximately 8.3 mcg group five major grass allergen), 300 IR (approximately 25 mcg), or 500 IR (approximately 42 mcg) . 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 . 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 . 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 . 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 (approximately 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 . Compared with those receiving placebo, active-treatment patients showed a 28 percent improvement in the primary efficacy measure of total combined symptom + medication score (difference versus placebo -0.13 [95% CI -0.19 to -0.06]). 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 adverse events 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 SLIT. 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 is approximately = 1 mcg) . 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 (difference versus placebo -1.58 [95% CI -2.8 to -0.36]) and 24 percent (difference versus placebo -2.04 [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.
In another study of ragweed SLIT-tablet, in which patients were randomized to two strengths of tablet (6 or 12 units of Amb a 1) or to placebo, a similar degree of improvement in TCS was demonstrated (21 and 27 percent, respectively) versus placebo during the peak season . The tablets were well tolerated, as the majority of treatment-related adverse events were mild and no systemic reactions were reported. One patient receiving the lower dose tablet did receive epinephrine for the sensation of localized pharyngeal edema. This points to the need to carefully educate patients on the types of adverse events that can occur with SLIT, and the importance of clearly outlining patient instructions on when to seek medical evaluation. It also raises the question of whether an epinephrine autoinjector should be prescribed to patients undergoing this form of self administered, home therapy.
Persistence of therapeutic benefit — The five-year double-blind, placebo-controlled discontinuation study with the Timothy grass tablet (Grastek) (three years of treatment followed by blinded assessment of symptom control in the two grass seasons following discontinuation of treatment) demonstrated a sustained treatment effect over two years of treatment [50,51], and has provide evidence of disease modification [51,52] as a result of long-term year-round therapy with Timothy grass SLIT. [50-52]. Hence, SLIT appears to be similar to SCIT with respect to conferring long-term clinical remission [53-58].
Sublingual drops — Another approach to the delivery of SLIT involves aqueous or glycerinated liquid allergen extracts that are initially held under the tongue for two to three minutes and then swallowed (ie, SLIT-drops). This construct has gained acceptance in Europe and is being studied in United States 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 .
A 2013 systematic review, which included 63 randomized controlled trials and 5131 subjects, was performed to determine if there was evidence that SLIT with aqueous or liquid drops, performed with products equivalent to those available in the United States for use in SCIT, were safe and effective for allergic asthma and rhinoconjunctivitis . Studies were only included if the methods could be replicated using allergen extracts available in the United States. 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-drops 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-drops are well tolerated. For allergic rhinitis and conjunctivitis, the quality of the evidence was deemed "moderate," as defined in the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) guidelines . The same analysis performed on studies of children found that the evidence that SLIT-drops improved asthma scores was of high quality, and the evidence that it improved allergic rhinitis and conjunctivitis scores was of moderate quality .
However, we believe that there are several factors limiting what can be learned from the above systematic review, including lack of standardized methods for conducting clinical trials, lack of uniformity regarding what defines a clinically meaningful effect, and variations in allergen selection (standardized versus nonstandardized allergens), allergen dose and duration of therapy. 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 [34,36,63].
Additional important limitations noted by the authors of the review, and which directly impact the ability of clinicians to create protocols with proven efficacy using SLIT-drops, 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 United States 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-drops that require further study before clinicians can be confident that SLIT-drops using available American products represent an effective alternative to SCIT . 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-drops, 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 [65-71]. These studies used the commercially available standardized glycerinated extracts licensed for SCIT. However, the data from most of 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) [65,66,71]. These clinical studies used the commercially available standardized glycerinated ragweed extract 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 . In this study, a modest (approximately 15 percent) improvement in the primary endpoint (the total rhinoconjunctivitis symptom score for the entire pollen season) was observed with both active treatment arms. However, this was not statistically significant.
In 2014, the first large-scale confirmatory clinical trial to demonstrate the efficacy of a sublingual liquid extract with a standardized (short ragweed) allergen extract was completed in North America. In this phase 3 clinical trial, 429 adults were randomized to either active treatment or placebo, with treatment initiated 8 to 16 weeks before and continued through the ragweed season . The study drug was administered sublingually, via a calibrated dropper, and held under the tongue for two minutes, with any residual liquid swallowed. Ninety-four percent of study subjects achieved the maximum tolerated dose (50 mcg Amb a 1). As consistent with accepted methods for assessment of SLIT studies, the primary endpoint was the total combined daily rhinoconjunctivitis symptom and medication scores, and the active treatment arm reported a 43 percent improvement in the primary endpoint as compared with the placebo group (difference versus placebo -0.83 [95% CI -1.30 to -0.37]). Expected increases in ragweed-specific IgG4, the predictive biomarker associated with symptom improvement in SCIT, were also observed in the active treatment group. No serious adverse events or anaphylaxis occurred. This North American study provides the first conclusive evidence that sublingual allergen immunotherapy with a liquid preparation, using well-established (standardized) allergen units (ie, mcg Amb a 1), can result in highly significant and clinically meaningful therapeutic benefit in the treatment of seasonal allergic rhinoconjunctivitis.
●Grass – In a multicenter, randomized trial of 207 children with grass pollen-induced rhinoconjunctivitis (with or without asthma), subjects received 40 mcg daily of grass pollen from six grass species or placebo in SLIT-drops, held under the tongue for three minutes and the swallowed . Treatment was administered daily January through August initially, and then all patients received daily active open-label treatment for two additional years. The primary endpoint was the change of the area under the curve of the symptom medication score (SMS) from the baseline season to the first season after start of treatment. The area under the curve of the SMS was approximately twofold lower in the active treated group). Allergen-specific IgG4 increased significantly in the active group also. No systemic allergic reactions occurred.
●House dust mite – SLIT-drops 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 [67,68,73]:
•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 allergen units (AU)/day or 70 mcg Der f1 per day), low-dose SLIT or placebo . 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 . 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-drops study investigated the immunologic biomarkers associated with treatment of grass- and dust mite-allergic patients with both sublingual preparations . The study demonstrated that treatment resulted in an increase in markers of tolerance (interleukin- 10 [IL-10] and transforming growth factor-beta (TGF-beta) with corresponding decreases in T helper 2 (Th2) inflammatory cytokines (IL-4/IL-13).
SAFETY — The European literature has provided extensive data on the safety of various forms of sublingual immunotherapy (SLIT) [74,75]. Well-designed clinical trials in Europe and North America are providing important safety information on research subjects receiving the newer sublingual constructs .
SLIT is safer than subcutaneous immunotherapy (SCIT), with fewer local and systemic allergic reactions. Serious systemic adverse events are uncommon to rare with SLIT, although a small number have been reported [77-79].
The grass pollen tablets available in the United States were not studied in patients already receiving SCIT or additional SLIT treatments and combining different forms of immunotherapy may increase likelihood of local or systemic reactions . Postmarketing surveillance data may provide additional information about the safety of initiating treatment in season, and reinitiating drug after missed doses.
Use in pregnancy — Published data addressing the safety of 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. The five-grass pollen sublingual tablet (Oralair, Stallergenes) was assigned a category B rating for use in pregnancy .
COMPLIANCE — Sublingual immunotherapy (SLIT) requires a commitment by the patient to a long-term daily maintenance therapy that is self administered, and compliance is likely to be lower than that obtained in supervised clinical trials.
A United States study reported an attrition rate of approximately 40 percent over four years .
Several European studies have assessed the compliance and adherence with SLIT:
●A study of 300 children (6 to 16 years of age), who received either grass or house dust mite sublingual drops or tablets over two years of treatment, revealed that discontinuation rates were clearly tied to follow-up visits to the study site . The drop-out rate was 30, 68, and 82 percent in patients evaluated in the clinic every three, six, and 12 months, respectively.
●Another study, which focused on young children (three to six years of age) reported that 46 percent of 150 children discontinued SLIT within three months of initiation . The most frequent reasons for discontinuation were lack of effect, time commitment, and adverse events.
●A third study addressed a more realistic measure of surveillance: drug sales figures (as opposed to marketing surveys, which can overestimate compliance due to contact of patients by the surveyor). In postmarketing surveys, compliance ranges from 50 to 90 percent depending on age and duration of treatment. In contrast, data on SLIT prescription refills shows a different picture: sales decreased from 100 percent to 44, 28, and 13 percent, in the first, second, and third years, respectively . Of the total prescriptions for SLIT from the two major manufacturers that participated in the survey, less than 20 percent of prescriptions were continued after three years.
●In a retrospective analysis of 6486 patients beginning subcutaneous immunotherapy (SCIT) or SLIT, 23 percent of SCIT patients, and 7 percent of SLIT patients completed three years of treatment .
Although these rates of treatment adherence are not dramatically different from those for other chronic diseases, they may significantly impact efficacy.
Noncompliance should not impact safety, provided patients are clearly instructed not to take extra doses in an attempt to "catch up" if they have had gaps in treatment. This may be particularly important at times when symptoms are severe. Long-term surveillance reporting will be needed to ascertain with the impact of stopping-restarting therapy.
PATIENTS WITH CONCOMITANT ASTHMA — Some trials have examined the safety and efficacy of sublingual immunotherapy (SLIT) in patients with rhinoconjunctivitis and concomitant asthma and suggest that SLIT is safe in many patients with milder asthma [67,72,85-90]. Information about patients with moderate persistent asthma as most studies excluded subjects requiring more than as needed bronchodilators or low-dose daily inhaled glucocorticoids [33,48,49]. This may be important, as 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 standardized-quality tablet (SQ-T) (15 mcg Phleum p 5), Timothy grass allergen sublingual tablet (Grazax), or placebo . 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 improvements in mean rhinoconjunctivitis symptom scores, medication scores, and well days (37, 41, and 54 percent, respectively) were 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 Phleum p 5]) was safe and effective, and did appear to have a positive impact on asthma symptoms and medication use .
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 .
In the grass tablet-treated group, the primary endpoints of median improvement of rhinoconjunctivitis symptom scores and medication scores were met . 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 SLIT AND SCIT
Advantages and disadvantages of SLIT — There are several potential advantages of sublingual immunotherapy (SLIT), compared with subcutaneous immunotherapy (SCIT):
●SLIT is safer, with fewer local and systemic allergic reactions than SCIT. (See 'Safety' above.)
●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 (or caregiver) 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 'Compliance' above.)
●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. Postmarketing 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.
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 . 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 [27,94-101]. Three randomized trials involved head-to-head, double-dummy protocols [27,94,95]. 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-drops 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 . 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 . 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-drops, SCIT, or placebo . 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 [102-104].
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 [34,76]:
●Can SLIT alter the progression of allergic disease? – No studies have yet addressed the question of whether oral forms of immunotherapy can be used to alter disease progression or prevent the onset of other allergic diseases. Specifically, it is not known if SLIT will prove to have the same potential to prevent the development of asthma in children that has been shown with SCIT. Until well-controlled clinical trials determine this, clinicians and parents may be unwilling to substitute SLIT for SCIT.
●Which patients are the best candidates for SLIT? – 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 . Thus, patient selection may be critical to outcome.
●What is the optimal duration of therapy? – Both SLIT [37,39,40,42,45,76,92] and SCIT [106-108] can produce clinical benefit within three to four months, and both appear to have some persistent benefit after therapy is discontinued, although the optimal duration of SLIT has yet to be defined. (See 'Persistence of therapeutic benefit' above.)
●How effective is SLIT for the polysensitized patient? – The most compelling data for use of SLIT is in the monosensitized pediatric or adult patient with seasonal allergic rhinoconjunctivitis, with or without mild asthma. Nearly all of 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 United States 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 . A modest positive trend was observed in clinical parameters in the multiple pollens group, which did not reach clinical significance.
However, a posthoc 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 . 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 SLIT (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.
●Safety considerations with real-world use – It will be important to follow postmarketing surveillance data to evaluate the safety of initiating treatment in season, and reinitiating drug after missed doses.
●Possible association with eosinophilic esophagitis – A possible association has been reported between eosinophilic esophagitis and SLIT with aeroallergens, as well as with oral immunotherapy with food allergens [110,111].
SUMMARY AND RECOMMENDATIONS
●Sublingual immunotherapy (SLIT) involves the application of allergen to the sublingual tissue. There are two forms of SLIT with inhalant allergens that have been widely studied: dissolvable sublingual tablets (SLIT-tablet) and sublingual allergen extracts (SLIT-drops). The most consistent results have been obtained with SLIT-tablet formulations. (See 'Sublingual allergen immunotherapy' above.)
●SLIT has been shown in randomized trials to be effective for allergic rhinitis (with or without conjunctivitis) and safe for patients with concomitant milder asthma. However, efficacy in reducing the symptoms of persistent, not well-controlled allergic asthma has not been conclusively demonstrated. (See 'Specific studies and efficacy data' above and 'Patients with concomitant asthma' above.)
●SLIT has been used in Europe and some other countries for decades for the treatment of allergic rhinoconjunctivitis. The first sublingual products, a five-grass pollen tablet and a single grass pollen tablet, became available in the United States in 2014. The Allergenic Products Advisory Committee (APAC) to the US Food and Drug Administration (FDA) has also recommended approval of a ragweed tablet. (See 'Availability' above.)
●SLIT is self administered by patients (or their caregivers) at home, although the initial dose is usually given under medical supervision. A significant percentage of patient experience local application site reactions (eg, oral pruritus, throat irritation, tongue swelling), but systemic allergic reactions are markedly fewer as compared with subcutaneous immunotherapy (SCIT). (See 'Methods' above.)
●The main advantages of SLIT over SCIT are safety and the comfort and convenience of an oral therapy that is self administered. SLIT appears to be somewhat less effective than SCIT, based upon meta-analyses and a small number of direct comparison studies. The main disadvantage of SLIT is that it requires the patient to be consistently compliant with therapy, and the impact of missed doses on efficacy is difficult to assess. (See 'Compliance' above and 'Comparison of SLIT and SCIT' above.)
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