Sublingual Immunotherapy for Children Allergic Diseases
Children Allergy Center, Jakarta Indonesia
Allergic diseases are on the rising trend and have reached epidemic proportions in developed countries. The main treatment options available are primarily symptomatic and do not “cure” the disease. The only specific treatment we can offer to patients is allergen avoidance, which, in the case of perennial allergens, like house dust mites, is impossible. Therefore, immunotherapy has been an attempt to get to the “root” of the problem by attempting to desensitize a patient and hence reduce their allergic symptoms. Sublingual Immunotherapy (SLIT) involves a dosing schedule of increasing amounts of allergen, much like the shots. However, rather than shots, the allergens are administered in a liquid or tablet form under the tongue.
The treatment of respiratory allergy is based on allergen avoidance, pharmacological treatment and immunotherapy. Immunotherapy is an allergen-oriented immunomodulator which affects the immune response to allergens, developing over a long period of time (months). The local routes, SLIT in particular, represent a significant advance because of the safety and good acceptance; it appears particularly suitable in paediatric patients, in which an optimal safety profile is required. Even though more studies are needed to gain insight into the mechanisms of action, the potential effect of SLIT over the mucosal regulation of the immune system may confer an additional rationale for its prescription. Nonetheless, the self-administration process needs careful instruction and a detailed follow-up of patients is required. Furthermore, prescription of SLIT must be made only by a specialist, after a detailed diagnosis has been established and the expected benefit/cost ratio has been carefully evaluated.
Allergen-specific immunotherapy, together with drug therapy and allergen avoidance, is a cornerstone in the management of respiratory allergy in both adults and children. At variance with drugs, immunotherapy affects the immunological response towards allergens at its earliest stages, and therefore it can be regarded as a biological response modifier. This means that immunotherapy can reduce symptoms and the need for rescue medications, but it can also alter to some extent the natural history of allergic disease. This fact has been well demonstrated during the last decade in several experimental studies. In particular, it has been shown that immunotherapy can prevent the inception of new sensitizations and the onset of asthma in children with allergic rhinitis. Furthermore, it was shown that immunotherapy could maintain its clinical efficacy for several years after discontinuation. Based on these observations, it is reasonable to regard immunotherapy as a particularly advantageous treatment in paediatric patients. In contrast, the traditional subcutaneous immunotherapy (SCIT) is burdened with the risk for severe adverse events, ranging from asthma and urticaria to anaphylaxis. The safety aspect was the major boost for the studies with noninjection or local immunotherapy, in particular those administered orally. The rationale for giving the allergen orally is that the gastrointestinal tract has an abundant mucosal immune system (gut associated lymphoid tissue) and therefore an effective antigen presentation can be expected. There are two modalities for administering the allergen orally: the oral route (oral immunotherapy, OIT) and the sublingual route (sublingual immunotherapy, SLIT). With SLIT, the extract is kept under the tongue for 1-2 min and then swallowed (sublingual swallow). whereas in OIT the allergen is immediately swallowed. The common aim of these methods is obviously to improve the safety and make the treatment more acceptable for the patients.
During the last 10 years, sublingual immunotherapy (SLIT) has been the subject of an impressive number of clinical trials that investigated different aspects of the treatment. Therefore, we have now available reliable data concerning the efficacy, the safety and the immunological aspects. It is also true that some points still need to be fully elucidated.
SLIT appears to have a favorable safety profile. In one review of the literature, the authors estimated that in approximately 1.2 million doses administered to 4400 patients, there were no serious, “life-threatening reactions”. There are reports of anaphylaxis with SLIT, but the incidence is rare. The primary symptoms reported by subjects receiving SLIT included mild “local” itching/burning of the mouth or lips, increase in rhinitis symptoms, gastrointestinal symptoms, and rarely, an increase in asthma symptoms. The reactions reported by subjects receiving SLIT were only significant enough to make the subject stop taking SLIT in less than 5% of the cases. SLIT has been studied in children as young as a year old. The primary symptoms reported by parents were oral itching, itchy skin, abdominal pain, and nausea and vomiting.
The effectiveness of SLIT has been studied in both adults and children. Some studies report that SLIT takes at least 2 years of treatment before subjects see improvement in symptoms. Other studies show improvement within a single year of therapy. One large review of over 100 SLIT research studies demonstrated that about 1/3 of studies showed significant improvement in symptoms while 1/3 showed no significant improvement. The variation in effectiveness had been attributed to the differences in the dose of allergen used for the various studies. In general, the higher doses of allergen appeared to have the largest impact on symptom improvement.
SLIT has potential to become a useful treatment of allergic rhinitis. Several questions need to be answered before SLIT can be used outside of the research domain. The optimal starting dose and dosing frequency for maintenance have not been established. It’s not clear if the starting/maintenance doses will be the same for all of the various allergens. Once the dosing questions have been addressed, the cost-effectiveness of SLIT needs to be established.
Allergen specific immunotherapy (SIT) is the practice of administering gradually increasing doses of the specific causative allergen to reduce the clinical reactivity of allergic subjects, and is the only treatment targeting the causes of hypersensitivity and not only the symptoms, as done by drugs . The traditional, subcutaneous immunotherapy (SCIT) was burdened by the problem of systemic reactions which may be sometimes severe and – though very rarely – even fatal. This was the background to develop non injections routes for SIT and particularly sublingual immunotherapy (SLIT), that emerged as a real treatment option for respiratory allergy
Sublingual Immunotherapy is method of allergy treatment that uses an allergen solution given under the tongue, which over the course of treatment, reduces sensitivity to allergens. Sublingual immunotherapy, or SLIT, has a very good safety profile and is given at home in adults and children. As more patients are treated with SLIT, additional side effects are being studied. A serious anaphylactic reaction occurred in a patient being treated with multiple allergens prepared from commercially available US extracts.
Immunotherapy is the process of desensitizing the body by gradually introducing it to allergy-causing dusts, molds, and pollens. Extracts of these allergens are mixed into a saline solution and introduced to the body through shots (subcutaneous) or under-the-tongue drops (sublingual). Over time, the concentration of these allergens is increased until the immune system learns to ignore them. As the immune system learns to tolerate these allergens, it will stop overreacting to them and allergies will go away.
The basis of sublingual immunotherapy is treatment of the underlying allergic sensitivity. Allergic symptoms improve as the allergic sensitivity improves. As a safe and effective method of treating the underlying disease, sublingual immunotherapy is capable of modifying the natural progression of allergic disease which can begin with allergic food sensitivities and eczema in young children and progress through allergic rhinitis and asthma in older children and adults.
A recent study, published in Allergy 2007: 62: 943–948, showed that a 3-year course of Sub-cutaneous immunotherapy had long-term clinical effects, by significantly reducing the development of asthma in children with allergic rhinoconjunctivitis up to 7 years after treatment. In a recent review of ALL studies on SLIT by the American Academy of Allergy, Asthma and Immunology published in Journal of Allergy and Clinical Immunology, 2007: 6: 1466-1468, 35% of studies resulted in significant reductions in medications and symptom scores but 38% of studies found no significant benefit from SLIT. When SLIT did work, it was typically less effective than with conventional subcutaneous injection immunotherapy and sometimes SLIT took two years to show significant clinical benefit.
Sublingual immunotherapy is taken as drops or tablets, placed under the tongue 3 or more times/week, containing a specific allergen which interacts with the immune system to decrease allergic sensitivity. Commonly the allergen is taken once a day. The antigen persists on the mucosal surface and is taken up by dendritic cells which interact with T lymphocytes (T-cells).
Sublingual immunotherapy takes advantage of each individuals ability to develop immunologic tolerance to non-pathogenic antigens such as those in foods and in resident bacteria. Consider the vast number of antigens we are exposed to every day which do not elicit an allergic response. Dendritic cells in the oral mucosa act as antigen presenting cells (APC) to T-cells in the cervical lymph nodes. This system modulates the allergic response by creating immune tolerance to antigens. The sublingual mucosa also has pro-inflammatory cells, such as mast cells, which is the reason that SLIT sometimes results in local reactions. The dose progression used is critical to the relative safety margin of sublingual therapy.
Early in treatment, sublingual dendritic cells secrete interleukin 10 (IL-10) which induces regulatory T cells to inhibit the inflammatory response. Long term changes that occur with immunotherapy include a decrease in mast cell sensitivity and a decrease in IgE production by B-cells. With sublingual immunotherapy there is a decrease in the IgE/IgG4 and a decrease in the TH1/TH2 ratio. Allergic symptoms improve as the underlying basis of the allergic disease improves.
Sublingual immunotherapy has been used for over 60 years worldwide. It is especially popular in Central Europe where the majority of patients receiving allergy treatment opt for sublingual immunotherapy (rather than shots). SLIT is rapidly gaining popularity in the United States. Specific immunotherapy has been practiced for almost 100 years. Classical immunotherapy by subcutaneous injection was demonstrated by Noon and Freeman in 1911. The oral route of immunotherapy was suggested earlier in 1900. Clinical attempts to determine the best dose and route for allergy therapy increased dramatically in the 1920s and 1930s. Injection of allergen became the standard therapy based in part on many scientific trials showing the effectiveness of that method for pollen, mold, dust mite, stinging insect, cat, and dog allergies. Injection therapy for foods resulted in a number of deaths and was abandoned by mid-century. Clinical use of sublingual immunotherapy for foods was described in 1969 by David Morris. Recent preliminary reports of success in inducing tolerance to peanuts and a few other foods are promising, but still investigational. SLIT was reintroduced in 1970 for inhalant allergens. Although some patients treated for food, pollen, pet dander and mold allergy by sublingual immunotherapy appeared to improve, the ideal dose, degree of expected improvement, and the mechanism by which improvement occurred was not established, and few studies were published in peer reviewed journals until the 1990s.
Controlled clinical trials first in Italy and later in England and throughout Europe have clearly shown the effectiveness of SLIT in the treatment of allergic rhinitis and asthma when due to one pollen. A few studies have been published in the US. The mechanisms involved have been studied, and the ideal dose range for some items (for example Timothy grass) have been established. In general SLIT is about 1/2 to 2/3 as effective as subcutaneous injection therapy, when optimal doses of a single pollen are used. Studies involving patients who require treatment with multiple pollens have shown less efficacy, and there is more concern about safety when multiple items are included in the treatment plan as well.
The practice of sublingual immunotherapy has been more available in Europe than in the United States. Concerns regarding the risks of oral and injection immunotherapy have always included death from anaphylaxis. Because of the higher risks of injection therapy in the 1980’s formal research into alternatives to injection therapy was supported in Europe. These studies demonstrated the relative safety and apparent effectiveness of sublingual immunotherapy, which resulted in widespread international acceptance of the method. In 1998 the World Health Organization concluded that sublingual immunotherapy was a viable alternative to the injection route and that its use in clinical practice is justified. Public acceptance facilitated the publication of new research. Between 1990 and 2005 more than 40 controlled trials with non-injection routes were published in peer-reviewed journals.
Today in Europe, sublingual immunotherapy accounts for 40 percent of allergy treatment. In the United States, although sublingual immunotherapy is being tried by some practitioners of allergy it is considered an investigational therapy. There is no FDA approved product or protocol, and the procedure must be paid for directly by the patient because neither the safety nor the efficacy of the procedure is considered established. For example, current Medicare guidelines state “For antigens provided to patients on or after November 17, 1996, Medicare does not cover such antigens if they are to be administered sublingually, i.e., by placing drops under the patient’s tongue. This kind of allergy therapy has not been proven to be safe and effective. Antigens are covered only if they are administered by injection.”
Mechanisms and Pharmacokinetics
Much is known about the possible mechanisms of action of SCIT, whereas SLIT has so far been studied mostly from a clinical point of view. Nevertheless, some interesting data have been published. First, SLIT has been demonstrated to be capable of reducing in vitro the proliferative response of T lymphocytes. Second, a significant modulator effect of SLIT on allergic inflammation (cell influx and intercellular adhesion molecule type 1 expression) could be observed in vivo both in the nose and the conjunctiva. Very recently, an open study in 10 children confirmed that SLIT was able to reduce intercellular adhesion molecule type 1 expression on nasal epithelial cells and to decrease methacholine responsiveness. A relevant effect of SLIT on immunoglobulins could be observed only in a few studies. Recent studies have found an association between respiratory allergy, particularly asthma, and the type of microbes and microbial products colonizing the gastrointestinal tract. Reduced colonization of the gastrointestinal tract with Gram-negative bacteria such as Lactobacillus strain in children and previous hepatitis A infection are associated with reduced prevalence of asthma, suggesting that the orofecal born gastrointestinal tract infections and the type of gastrointestinal microflora could play a role in the maturation of the immune system, having an influence on the regulation of the respiratory immune response. It has been suggested that both OIT and SLIT may use mucosal tolerance mechanisms, and they potentially could elicit allergen-specific tolerance and immune deviation through regulatory T cells.
Very recently, the pharmacokinetics of local routes were studied in humans using a radiolabelled purified allergen (Par j 1) and a special procedure. After the administration (oral, sublingual or intranasal) of the 123I-radiolabeled allergen, sequential scintiscans, plasma radioactivity and plasma chromatographies were evaluated at different times. It was observed that no direct absorption of the allergen through the mucosae occurs: plasma radioactivity increased only after the allergen was swallowed. Moreover, the allergen was retained for long periods of time (up to 40 h) at mucosal level, both in the nose and the mouth. Finally, the gastrointestinal absorption was relevant, but no trace of the native allergen could be detected in the bloodstream, whereas if a modified allergen was administered, traces of it could be detected in the plasma. Similar results were subsequently obtained in allergic volunteers using a commercial preparation. These data suggest that the contact of the allergen with the oral mucosa is critical and that the allergen is not absorbed in the mouth.
In the world-renowned Cochrane Review, a meta-analysis reviewed 22 studies involving 979 patients on sublingual immunotherapy and concluded that sublingual immunotherapy is a safe treatment which reduces symptoms and medication requirements in allergic rhinitis. SLIT is also endorsed by the World Health Organization and the ARIA (Allergic Rhinitis and its Impact on Asthma) guidelines. In addition, our studies show that more than 80 percent of allergic patients and more than 90 percent of asthmatics report symptom relief within the first few months of using AllergyEasy.
While many patients experience symptom relief in a matter of weeks, it can take up to three to five years to completely “re-train” the immune system for life. SLIT is a perfect program for travelers such as pilots, members of the military, etc. Sublingual immunotherapy (drops) have distinct advantages over subcutaneous immunotherapy (shots) when traveling. SCIT requires that the patient remains in the office after the injection for thirty minutes to monitor for potential side effects. With SLIT, the patient can take the serum on the road with him/her. All of our bottles are under three ounces, making them perfect for travelers. Additionally, AllergyEasy’s comprehensive serum safeguards patients from the world’s major allergens. Patients are protected wherever they go.
Comparison to other regimens
Options for managing allergy include avoiding what you’re allergic to, such as not eating a food you have a known problem with, avoiding pets, etc. Many allergens are unavoidable due to the widespread nature of dust, molds, pollens, weeds, and various food elements in packaged and processed foods. A limitation of avoidance is that low levels of exposure to antigens allows the immune system to modulate the allergic sensitivity through T regulatory cells which are short lived. The allergic sensitivity persists much longer so that intermittent exposure is more problematic than frequent low level exposure.
Symptomatic treatment options for allergies include over the counter medications such as antihistamines, prescription oral medication, nasal sprays and short-term prednisone. Biologics such as anti-IgE anti-bodies have been used in severe cases. While there is a role for all of these options, Allergy immunotherapy is the only treatment directed at resolving the underlying cause of allergy symptoms.
Currently, immunotherapy is offered via allergy injections (allergy shots) for inhalation allergies although not for foods. Sublingual immunotherapy (allergy drops and tablets) is offered for inhalation allergies and foods. Like injection therapy, sublingual immunotherapy directly changes the body’s ability to react with allergens. Following successful treatment with immunotherapy, allergy symptoms are less apparent or at least less problematic.
There has been no life-threatening adverse events nor fatalities reported with SLIT since its introduction in 1986. The most frequent side-effects reported are local, including sublingual itch or swelling and nausea or abdominal pain. These are mild and self-limiting and usually disappear with a temporary reduction in the SLIT dose. The occurrences of side-effects are reported to be even lower in children. Moreover, the drop-out rate due to side-effects is very rare. In children, the overall incidence of side-effects has been reported to be 3% or 1 in 12,000 doses and no discontinuation of treatment was needed
SLIT does not carry the same risks of anaphylactic reaction that shots do. To date, there have been no life-threatening adverse events associated with SLIT. This makes SLIT a perfect option for those that may not be candidates for allergy shots (severe asthmatics, small children, etc.) While many allergists won’t start children on allergy shots until age 7, even infants can safely take oral drops. Unlike shots, oral drops are not associated with life-threatening anaphylactic reactions. In addition, the serum is all-natural, consisting of the same elements we breathe in daily in our environment.
Because sublingual drops are used several times per week, it is necessary to take them at home. This is in contrast to injection therapy, which should always be taken in a medically supervised setting due to the know risks of anaphylaxis (about 1/2000) and death (about 1/2,500,000).
In the early years of SLIT local sensitivities were reported in many patients (oral itching, intestinal disturbances) but these could usually be managed by dose adjustments. Although as of July 2009 no deaths have been reported from SLIT (and many millions of doses have been taken), numerous cases of anaphylaxis have now been reported. In one study, for example, sixty patients who ranged in age from 6 to 50 years were treated over a 90-day period with a progressive dose of dust mite antigens via SLIT. In this small study alone there were seven systemic reactions (meaning, atopy, a reaction that occurs thorough the whole body, not just where the allergen is applied). All reactions were associated with wheezing or worsening nasal symptoms, and one patient had angioedema and urticaria
Advantages and disadvantages of SLIT
Subcutaneous immunotherapy (SCIT) has been practiced, with good results, for many years. However, it is fraught with the risk of adverse side-effects including fatalities. The rate of occurrence of severe systemic (near-fatal) adverse events with SCIT ranges from 0.5%-6% and the occurrence of systemic reaction in general has been reported to be up to 46.7%. Moreover, this injection-based modality of administration is not acceptable to most paediatric patients. Hence, there has been a move to search for other noninjection routes of immunotherapy including local nasal, local bronchial, oral and sublingual (SLIT) immunotherapy. Of these routes, SLIT holds the most promise. As compared to SCIT, another advantage of SLIT is the perceived improvement of compliance when patients are administered the immunotherapy using this route. Lombardi et al reported a remarkably high adherence rate of 97% in patients using SLIT. In contrast, the rate of discontinuation of SCIT has been reported to be up to 34%, mainly due to side-effects. The global cost of SLIT has also been reported to be lower than SCIT(. As such, it is now accepted as a viable route of immunotherapy for adults and children by the World Health Organization (WHO), European Academy of Allergology and Clinical Immunology (EAACI)(and also in the Allergenic Rhinitis and its Impact on Asthma (ARIA) document
There are several potential advantages of SLIT, 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 .
- All-natural and safer than shots (no severe reactions)
- Administered at home
- Unlike medications, SLIT treats the source of the problem (not just the symptoms)
- Great for all ages—infants to seniors
- Avoids children’s fear of shots and needles
- Less costly/fewer physician visits
- Great for travelers (“portable serum,” protects against all the world’s major allergens)
- Simple testing process
- SLIT is more comfortable for patients, since allergens are ingested rather than injected.
- SLIT is more convenient for patients and clinicians, because therapy is self-administered by the patient at home.
- Less time is required to achieve a therapeutic effect with OIT, since benefit can be observed within 3 to 4 months, compared with 4 to 6 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.
- 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.
SLIT is prepared in drops or tablets in different concentrations. It is kept under the tongue for 1-2 minutes and then swallowed. It is usually given on an empty stomach in the morning. The dosing involves an escalating-dose phase followed by a maintenance phase. The escalating-dose phase usually takes 4-6 weeks with increasing concentrations of allergens administered daily. During the maintenance dose phase, the maximum dose is administered 1-3 times a week. Schedules differ depending on the manufacturers. For perennial allergens like HDM, SLIT is administered continuously in contrast to pollen allergy, where administration may be preseasonally and seasonally. There have been proposals to speed-up the escalating-dose phase to simplfy the regime and this fast-induction regime has been shown to have similar side-effect profiles(
Safety in Children
In the published trials, the most frequently reported side effect was oral/sublingual itching after taking the dose, followed by nonspecific gastrointestinal complaints (nausea, vomiting, abdominal pain). These side effects were always described as mild and self-resolving, and infrequently caused dropouts. In the recent paediatric studies, the occurrence of side effects was negligible and they were not troublesome. In a single study a significant rate of gastrointestinal complaints was reported, but in this study the amount of allergen was as high as 375 times the amount usually administered in a standard SCIT course. Headache, rhinorrhea, constipation or urticaria have been reported only sporadically and their incidence did not differ from the placebo groups . Noticeably, no severe systemic adverse event was reported in the literature over 15 years. André et al. recently reviewed the safety aspects of the controlled trials performed with the vaccines of a single manufacturer. Six hundred and ninety patients were enrolled (347 active + 343 placebo), with 218 children (103 active + 115 placebo). Overall, adverse events had a similar occurrence in active and placebo, with the exception of the oral and gastrointestinal side effects, which were more frequent in SLIT patients, although mild. In contrast, the occurrence of side effects and dropouts did not differ in adults and children. More consistent information on the safety can be obtained when SLIT is prescribed and administered in everyday clinical practice. Di Rienzo et al. performed a post-marketing surveillance study in 268 children aged between 2 and 15 years and receiving SLIT for up to 3 years. These authors showed that the overall incidence of systemic side effects was 3% of the patients and 1/12 000 doses. Out of eight side effects, only one (urticaria) was moderate and required treatment with oral antihistamines. Overall, discontinuation of the treatment was never required. Finally, the possible effects of the sublingual administration of allergens in children was investigated by measuring the mucosal level of tryptase and eosinophil cationic protein (ECP): no change in the levels of these mediators could be detected at all, even in one patient reporting oral itching after SLIT intake
Clinical efficacy in Children
SLIT was first investigated in a double-blind placebo-controlled trial in 1986 and, to date, 22 trials conducted with adequate methods have been published, testifying to the rapid development of interest in this mode of administration. Nineteen out of 22 studies confirmed the clinical efficacy of SLIT in rhinitis induced by common allergens (grass, mites, birch and parietaria), and some studies also showed a significant effect on asthma. The magnitude of clinical efficacy ranged between about 20 and 50% – quite superior to an eventual placebo effect.
SLIT was investigated in paediatric patients in seven studies : four with mites, three with parietaria, olive and grasses. All studies, but one, reported a significant clinical efficacy of SLIT in reducing both symptoms and drug intake. Moreover, in some of the studies a measurable effect on skin reactivity or specific provocation tests was also reported. Of particular note, in a study conducted on asthmatic children treated for 2 years with mite extract, the decrease in symptoms and drug intake reached 60% on reaching the second year of treatment.
Clinical efficacy of SLIT in Allergic Rhinitis
There have been 25 double-blind placebo controlled trials to date on SLIT in AR. Eight of them have been conducted in children. All studies except 3 demonstrated a clear reduction in clinical symptoms and medication scores from 20% to 60%. A recent meta-analysis of 22 randomized, placebo-controlled trials involving 979 patients also concluded that SLIT is both safe and efficacious in symptom reduction as well as medication reduction. Overall, SLIT is less effective in HDM allergic patients as compared to pollen sensitive ones. The duration of treatment seems to be important in HDM SLIT where studies that last at least 2 years are the ones that give positive results.
Clinical efficacy of SLIT in Asthma
The use of SLIT in asthma is not as clear as there have been fewer studies to date. However, the few studies that have been conducted showed a reduction in the use of beta-2 agonists, systemic steroids ingestion, days with asthma symptoms as well as overall clinical symptoms and quality of life.
Efficacy of SLIT in HDM allergic children
A recent systematic review on SLIT in children showed that in AR, a significant effect was demonstrated in 2 studies and no effect in another 2 studies. For asthma, 5 studies were reviewed and all of them showed an improvement in asthma symptoms but the efficacy observed seems to be additional to HDM preventive measures. It is not known why SLIT improves asthma symptoms in children but not clear results with AR. They concluded that SLIT should be used in children more than 4 years of age suffering from mild to moderate persistent asthma due to monosensitisation to HDM. The effects on symptoms and drug consumption are deemed to be low to moderate and additive to the efficacy of preventative measures.
SCIT has been demonstrated to have a lasting effect after discontinuation of treatment(24) but this effect is still unknown for SLIT. There has been one study in children which demonstrated this positive phenomenon. Thirty-five children with AR due to HDM allergy and 25 controls were studied. They were given a 4-5 year course of SLIT. The SLIT group showed significant difference versus baseline for the presence of asthma (p<0.001) and use of asthma medications (p<0.01) even 5 years after discontinuation but there was no difference in control group(25). However, further long-term studies will need to be conducted to substantiate this finding
SCIT has been shown to be capable of modifying the natural history of the disease (i.e. the onset of asthma in rhinitis patients) and of preventing the onset of new sensitizations. Moreover, a long-lasting effect of SCIT after discontinuation has been repeatedly seen in several clinical trials. At present, such demonstrations are still lacking for local routes, since SLIT has been used routinely only in the last 10 years. We performed a prospective parallel group controlled study in 60 children (mean age 8.5 years) suffering from allergic asthma/rhinitis due to mites. Thirty-five underwent a 4-5 year course of SLIT with standardized extract, and 25 received only drug therapy. The patients were evaluated at baseline, at the end of SLIT and 4-5 years later. In the SLIT group, we found a significant difference versus baseline regarding the presence of asthma (P < 0.001) and the use of asthma medications (P < 0.01) even 5 years after discontinuation, whereas no difference was observed in the control group
Immunotherapy Recommendations of WAO
To reduce risk and improve efficacy of SLIT, the WAO recommends the following considerations for starting immunotherapy:
- There should be the presence of a demonstrated immunoglobulin E (IgE)–mediated disease, with positive skin test results and serum-specific IgE to an allergen concordant with clinical symptoms.
- There should be documentation that the symptoms can be explained by specific sensitivity, based on appearance of symptoms related to exposure to the allergen(s) identified by allergy testing. Optional confirmation may include allergen challenge with the relevant allergen(s).
- Severity and duration of symptoms should warrant use of SLIT, with confirmation from objective parameters such as missing time from work or school. For rhinoconjunctivitis, patients should have subjective symptoms of sufficient severity and duration. For asthma, the control questionnaire should not show uncontrolled asthma, and pulmonary function testing is required to exclude patients with severe asthma. Pulmonary function should be monitored during therapy.
- SLIT therapy should only be started in settings where standardized or high-quality vaccines are available. Only specialists should prescribe specific immunotherapy. Subcutaneous immunotherapy should be administered only by physicians trained to manage systemic reactions if anaphylaxis occurs.
- Although SLIT is administered at home, patients should be educated regarding possible risks and how to control adverse effects that may develop.
- Patients with a single allergen sensitivity are more likely to benefit from specific immunotherapy vs patients sensitive to multiple allergens, but more data are needed in this area.
- Specific immunotherapy will not benefit patients with nonallergic triggers.
- For safety reasons, asthmatic patients must be asymptomatic when receiving SLIT injections. Asthmatic patients with severe airways obstruction are more likely to have lethal adverse reactions.
- To maximize the efficacy and safety of SLIT in asthmatic patients, forced expiratory volume in 1 second with pharmacologic treatment should reach at least 70% of predicted values.
- SLIT 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. The immunologic changes that result from oral allergen immunotherapy appear to be similar to those induced by injection immunotherapy. 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. The efficacy and safety of SLIT has been demonstrated in high quality randomized trials in both Europe and the United States, in both children and adults. The small number of studies that have included patients with concomitant asthma found that OIT was generally well-tolerated. However, SLIT has not been demonstrated to have clear benefit in the treatment of allergic asthma.
- The clinical efficacy of SLIT in both asthma and rhinitis is now supported by numerous controlled trials. For this reason, the initial scepticism is progressively declining and SLIT is becoming, at least in principle, an ‘official’ treatment. Of course, the clinical efficacy and safety of SLIT have been confirmed in paediatric patients, although the demonstration of a preventive effect similar to that of SCIT is still lacking. In contrast, the long-lasting effect in children has been well ascertained; therefore, the use of this modality of immunotherapy can be considered, overall, to be advantageous, especially when the optimal safety profile is taken into account.
- SLIT was successfully introduced in Europe mainly on safety grounds and in some countries, including Italy, is currently more frequently employed than SCIT. The analysis of the abundant literature supports the use of SLIT in children with rhinitis and asthma caused by sensitization to seasonal allergens, while further studies are needed to demonstrate a full effectiveness in sensitization to perennial allergens. Favourable data obtained from studies on compliance and cost-effectiveness make SLIT a feasible treatment for treatment with respiratory allergy.
- Bousquet, J. Sublingual immunotherapy: validated. Allergy 2006; 61(supplement 81):5.
- Frati, F, Moingeon, P, Marcucci, F, et al. Mucosal immunization application to allergic disease: sublingual immunotherapy. Allergy Asthma Proc 2007; 28:35.
- Noon L. Prophylactic inoculation for hay fever. Lancet 1991;1:1572.
- Adkinson NF, Eggleston PA, Eney D, et al. A controlled trial of immunotherapy for asthma in allergic children. NEJM 1997;336:324-331.
- Creticos PS, Van Metre TE, Mardiney MR, et al. Dose response of IgE and IgG antibodies during ragweed immunotherapy. JACI 1984;73:94-104.
- Rocklin RE, Sheffer AL, Greineder DK et al. Generation of antigen-specific suppressor cells during allergy desensitization. N Engl J Med1980;302(22):1213-9.
- Till SJ, Durham SR. Immunological responses to allergen immunotherapy. Clin Allergy Immunol. 2004;18:85-104.
- Akdis CA, Blaser K. Mechanisms of allergen-specific immunotherapy. Allergy 2000; 55:522-530.
- Purello-D’Ambrosio F, Gangemi S, Merendino RA, et al. Prevention of new sensitizations in monosensitized subjects submitted to specific immunotherapy or not: a retrospective study. Clin Exp Allergy 2001; 31:1295-1302.
- Pajno G, Barberio G, De Luca F, et al. Prevention of new sensitizations in asthmatic children monosensitized to house dust mite by specific immunotherapy: a six-year follow-up study. Clin Exp Allergy 2001; 31:1392-1397.
- Moller C, Dreborg S, Ferdousi HA, et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J Allergy Clin Immunol 2002; 109:251-256.
*The first controlled study formally demonstrating the preventive effect of immunotherapy.
- Durham SR, Walker SM, Varga EM, et al. Longterm clinical efficacy of grass pollen immunotherapy. N Eng J Med 1999; 341:468-475.
- Eng PA, Reinhold M, Gnehm HP. Long-term efficacy of preseasonal grass pollen immunotherapy in children. Allergy 2002; 57:306-312.
*A controlled study showing the long-lasting efficacy of immunotherapy in paediatric patients.
- Lockey RF, Nicoara-Kasti GL, Theodoropoulos DS, Bukantz SC. Systemic reactions and fatalities associated with allergen immunotherapy. Ann Allergy Asthma Immunol 2001; 87 (Suppl 1): 47-55.
*A comprehensive systematic review on the safety of SCIT.
- Laissue JA, Chappuis BB, Muller C, et al. The intestinal immune system and its relation to disease. Dig Dis 1993; 11:298-312.
- Bousquet J, Lockey R, Malling HJ, editors. World Health Organization Position Paper. Allergen immunotherapy: therapeutical vaccines for allergic diseases. Allergy 1998; 53 (Suppl): 20-22.
- Malling HJ, editor. European Academy of Allergology and Clinical Immunology (EAACI) Position Paper on local immunotherapy. Allergy 1998; 53: 933-944.
- Bousquet J, Van Cauwenberge P, editors. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol 2001; 107 (Suppl): S240-S245.
**This recent evidence-based document encompasses all the diagnostic and therapeutic aspects of respiratory allergy. It also reports the updated indications for SLIT and local immunotherapies.
- Taudorf E, Weeke B. Orally administered grass pollen. Allergy 1983; 38:561-564.
- Urbanek R, Gehl R. Efficacy of oral immunotherapy for house dust mite allergy [in German]. Monatssch Kinderheilkd 1982; 130:150-152.
- Cooper PJ, Darbyshire , Nunn AJ, Warner JO. A controlled trial of oral hyposensitization in pollen asthma and rhinitis in children. Clin Allergy 1984; 14:541-550.
- Taudorf E, Laursen LC, Djurup R, et al. Oral administration of grass pollen to hay fever patients: an efficacy study in oral hyposensitization. Allergy 1985; 40:321-335.
- Moller C, Dreborg S, Lanner A, Bjorksten B. Oral immunotherapy of children with rhinoconjunctivitis due to birch pollen allergy. Allergy 1986; 41:271-279.
- Taudorf E, Laursen CL, Lanner A, et al. Oral immunotherapy to birch pollen hay fever. J Allergy Clin Immunol 1987; 80:153-161.
- Mosbech H, Dreborg S, Madsenn F, et al. High dose grass pollen tablets used for hyposensitization in hay fever patients: a one year double blind placebo controlled study. Allergy 1987; 42:451-455.
- Giovane A, Bardare M, Passalacqua G, et al. A three year double blind placebo-controlled study with specific oral immunotherapy to Dermatophagoides: evidence of safety and efficacy in pediatric patients. Clin Exp Allergy 1994; 24:53-59.
- Oppenheimer J, Areson JG, Nelson HS. Safety and efficacy of oral immunotherapy with standardized cat extract. J Allergy Clin Immunol 1994; 93:61-67.
- Van Deusen MA, Angelini BL, Cordoro KM, et al. Efficacy and safety of oral immunotherapy with short ragweed extract. Ann Allergy Asthma Immunol 1997; 78:573-580.
- Litwin A, Flanagan M, Entis G, et al. Oral immunotherapy with short ragweed in a novel encapsulated preparation: a double blind study. J Allergy Clin Immunol 1997; 100:30-38.
- Scadding K, Brostoff J. Low dose sublingual therapy in patients with allergic rhinitis due to dust mite. Clin Allergy 1986; 16:483-491.
- Tari MG, Mancino M, Monti G. Efficacy of sublingual immunotherapy in patients with rhinitis and asthma due to house dust mite: a double blind study. Allergol Immunopathol 1990; 18:277-284.
- Sabbah A, Hassoun S, Le Sellin J, et al. A double blind placebo controlled trial by the sublingual route of immunotherapy with a standardized grass pollen extract. Allergy 1994; 49:309-313.
- Feliziani V, Lattuada G, Parmiani S, Dall’Aglio PP. Safety and efficacy of sublingual rush immunotherapy with grass allergen extracts: a double blind study. Allergol Immunopathol 1995; 23:173-178.
- Troise C, Voltolini S, Canessa A, et al. Sublingual immunotherapy in parietaria pollen induced rhinitis: a double blind study. J Invest Allergol Clin Immunol 1995; 5:25-30.
- Hirsch T, Sahn M, Leupold W. Double blind placebo controlled study of sublingual immunotherapy with house dust mite extracts in children. Pediatr Allergy Immunol 1997; 8:21-27.
- Clavel R, Bousquet J, André C. Clinical efficacy of sublingual swallow immunotherapy: a double blind placebo controlled trial of a standardized five grass pollen extract in rhinitis. Allergy 1998; 53:493-498.
- Horak F, Stubner UE, Berger U, et al. Immunotherapy with sublingual birch pollen extract: a short term double blind study. J Invest Allergol Clin Immunol 1998; 8:165-171.
- Vourdas D, Syrigou E, Potamianou P, et al. Double blind placebo controlled evaluation of sublingual immunotherapy with a standardized olive tree pollen extract in pediatric patients with allergic rhinoconjunctivitis and mild asthma due to olive tree pollen sensitization. Allergy 1998; 53:662-671.
- Hordijk GJ, Antwelink JB, Luwema RA. Sublingual immunotherapy with a standardized grass pollen extract: a double blind placebo controlled study. Allergol Immunopathol 1998; 26:234-240.
- Passalacqua G, Albano M, Fregonese L, et al. Randomised controlled trial of local allergoid immunotherapy on allergic inflammation in mite induced rhinoconjunctivitis. Lancet 1998; 351:629-632.
- Passalacqua G, Albano M, Riccio AM, et al. Clinical and immunological effects of a rush sublingual immunotherapy to parietaria species: a double blind placebo controlled trial. J Allergy Clin Immunol 1999; 104:964-968.
- Bousquet J, Scheinmann P, Guinnepain MT, et al. Sublingual swallow immunotherapy (SLIT) in patients with asthma due to house dust mites: a double blind placebo controlled study. Allergy 1999; 54:249-260.
- Purello d’Ambrosio F, Gangemi S, Isola S, et al. Sublingual immunotherapy: a double blind placebo controlled trial with Parietaria judaica extract standardized in mass units in patients with rhinoconjunctivitis, asthma or both. Allergy 1999; 54:968-973.
- Pradalier A, Basset D, Claudel A, et al. Sublingual swallow immunotherapy (SLIT) with a standardized five grass pollen extract (drops and sublingual tablets) versus placebo in seasonal rhinitis. Allergy 1999; 54:819-828.
- La Rosa M, Ranno C, André C, et al. Double blind placebo controlled evaluation of sublingual swallow immunotherapy with standardized parietaria judaica extract in children with allergic rhinoconjunctivitis. J Allergy Clin Immunol 1999; 104:425-432.
- Guez S, Vatrinet C, Fadel R, André C. House dust mite sublingual swallow immunotherapy in perennial rhinitis: a double blind placebo controlled study. Allergy 2000; 55:369-375.
- Pajno GB, Morabito L, Barberio G, Parmiani S. Clinical and immunological effects of longterm sublingual immunotherapy in asthmatic children sensitized to mite: a double blind study. Allergy 2000; 55:842-849.
- Caffarelli C, Sensi LG, Marcucci F, Cavagni C. Preseasonal local allergoid immunotherapy to grass pollen in children: a double-blind, placebo-controlled, randomized trial. Allergy 2000; 55:1142-1147.
- Ariano R, Spadolini I, Panzani RC. Efficacy of sublingual specific immunotherapy in Cupressaceae allergy using an extract of Cupressus arizonica: a double blind study. Allergol Immunopathol 2001; 29:238-244.
- Bahcecilier NN, Isik U, Barlan IB, Basaran N. Efficacy of sublingual immunotherapy in children with asthma and rhinitis: a double-blind, placebo-controlled study. Pediatr Pulmonol 2001; 32:49-55.
- Voltolini S, Modena P, Minale P, et al. Sublingual immunotherapy in tree pollen allergy: double blind, placebo controlled study with a biologically standardized extract of tree pollen (alder, birch and hazel) administered by a rush schedale. Allergol Immunopathol 2001; 29:103-110.
- Lima MT, Wilson D, Pitkin L, et al. Grass pollen sublingual immunotherapy for seasonal rhinoconjunctivitis: a randomized controlled trial. Clin Exp Allergy 2002; 32:507-514.
*A rigorous and detailed study on the efficacy of SLIT and its local and systemic immunological effects.
- André C, Vatrinet C, Galvain S, et al. Safety of sublingual swallow immunotherapy in children and adults. Int Arch Allergy Immunol 2000; 121:229-234.
- Di Rienzo V, Pagani A, Parmiani S, et al. Post-marketing surveillance study on the safety of sublingual immunotherapy in children. Allergy 1999; 54:1110-1113.
- Marcucci F, Sensi L, Frati F, et al. Sublingual tryptase and ECP in children treated with grass pollen sublingual immunotherapy (SLIT): safety and immunologic implications. Allergy 2001; 56:1091-1095.
**An interesting immunological approach to the safety aspects of SLIT, showing the absence of a local provocative effect of the treatment.
- Fanta C, Bohl B, Hirt W, et al. Systemic immunological changes induced by administration of grass pollen extract via oral mucosa during SLIT. Int Arch Allergy Immunol 1999; 120:218-224.
- Silvestri M, Spallarossa D, Battistini E, et al. Changes in inflammatory and clinical parameters and in bronchial hyperreactivity asthmatic children sensitized to house dust mites following sublingual immunotherapy. J Investig Allergol Clin Immunol 2002; 12:52-59.
*A controlled study approaching the effects of SLIT in children from a functional viewpoint.
- Bjorksten B, Naaber P, Sepp E, Mikelsaar M. The intestinal microflora in allergic Estonian and Swedish 2-year-old children. Clin Exp Allergy 1999; 29:342-346.
- Matricardi PM, Rosmini F, Ferrigno L, et al. Cross-sectional retrospective survey of the prevalence of atopy among Italian military students with antibodies against hepatitis A. BMJ 1997; 314:999-1003.
- Matricardi PM, Rosmini F, Riondino S, et al. Exposure to foodborne and orofecal microbes versus airborne viruses in relation to atopy and allergic asthma: epidemiological study. BMJ 2000; 320:412-417.
- Umetsu DT, McIntire J, Akbari O, et al. Asthma: an epidemic of dysregulated immunity. Nature Immunol 2002; 3:715-720.
**This article reviews the hygiene hypothesis and the mechanisms involved in immune tolerance or its loss and the role of T regulatory cells – an important field of research strictly related to mucosal immunotherapies.
- Bagnasco M, Mariani G, Passalacqua G, et al. Absorption and distribution kinetics of the mayor Parietaria allergen administered by noninjectable routes to healthy human beings. J Allergy Clin Immunol 1997; 100:121-129.
- Bagnasco M, Passalacqua G, Villa G, et al. Pharmacokinetics of an allergen and a monomeric allergoid for oromucosal immunotherapy in allergic volunteers. Clin Exp Allergy 2001; 31:54-60.
*A novel approach to the pharmacokinetics of sublingual immunotherapy.
- Passalacqua G, Canonica GW. Long lasting efficacy of specific immunotherapy. Allergy 2002; 57:275-276.
*A short but complete review on the long-lasting effect of immunotherapy.
- Di Rienzo V, Marcucci F, Puccinelli P,et al.. Long lasting effect of sublingual immunotherapy in children with asthma due to house dust mite: a ten year prospective study. Clin Exp Allergy (in press).
- Grosclaude M, Bouillot P, Alt R, et al. Safety of various dosage regimens during induction of sublingual immunotherapy. Int Arch Allergy Immunol 2002; 129:248-253.
- Passalacqua G, Canonica GW. Alternative routes of immunotherapy: a review. J Invest Allergol Clin Immunol 1996; 36:81-87.
- Kagi MK, Wutrich B. Different methods of local allergen immunotherapy. Allergy 2002; 57:379-388.
**An updated review of the available studies of SLIT and mucosal immunotherapies, with a detailed overview on the immunological rationale for mucosal desensitization.
- Frew AJ, White PJ. Sublingual immunotherapy. J Allergy Clin Immunol 1999; 104:267-270.
- Frew AJ, Smith HE. Sublingual immunotherapy. J Allergy Clin Immunol 2001; 107:441-444.
*A critical discussion of the available experimental data on SLIT.
- Brown JL, Frew AJ. The efficacy of oromucosal immunotherapy in respiratory allergy. Clin Exp Allergy 2001; 31:8-10.
- Douglass J, O’Heir R. Specific allergen immunotherapy: time for alternatives? Clin Exp Allergy 2002; 32:1-3.
- Committee on the safety of medicines. CSM update: desensitizing vaccines. Br Med J 1986;293:948.
- Canonica GW, Passalacqua G. Noninjection routes for immunotherapy. J Allergy Clin Immunol. 2003;111(3):437-48
- Steward GE, Lockey RF. Systemic reactions from allergen immunotherapy. J Allergy Clin Immunol 1992;90:567-78.
- Lombardi C, Gani F, Landi M, et al. Quantitative assessment of the adherence to sublingual immunotherapy. J Allergy Clin Immunol 2004;113(6):1219-20.
- Lower T, Henry J, Mandik L, et al. Compliance with allergen immunotherapy. Ann Allergy. 1993;70(6):480-2.
- Bousquet J, Lockey R, Malling HJ, et al. Allergen immunotherapy: therapeutic vaccines for allergic diseases. World Health Organization. American academy of Allergy, Asthma and Immunology. Ann Allergy Asthma Immunol. 1998 Nov;81(5 Pt 1):401-5.
- Malling HJ. The position of immunotherapy in the European Academy of Allergology and Clinical Immunology. J Investig Allergol Clin Immunol. 1997;7(5):356-7.
- Bachert C, van Cauwenberge P, Khaltaev N. Allergic rhinitis and its impact on asthma. In collaboration with the World Health Organization. Executive summary of the workshop report. 7-10 December 1999, Geneva, Switzerland. Allergy. 2002;57(9):841-55.
- Grosclaude M, Bouillot P, Alt R, et al. Safety of various dosage regimens during induction of sublingual immunotherapy. A preliminary study. Int Arch Allergy Immunol. 2002;129(3):248-53
- Passalacqua G, Guerra L, Pasquali M, et al. Efficacy and safety of sublingual immunotherapy. Ann Allergy Asthma Immunol 2004;93:3-12
- Sopo SM, Macchiaiolo M, Zorzi G, et al. Sublingual immunotherapy in asthma and rhinoconjunctivitis; systematic review of paediatric literature. Arch Dis Child 2004;89:620-624
- Wilson DR, Torres LI, Durham SR. Sublingual immunotherapy for allergic rhinitis (Cochrane Review). Cochrane Database Syst Rev. 2003;2:CD002893
- Bousquet J, Lockey R, Malling HJ. Allergen immunotherapy: therapeutic vaccines for allergic diseases. A WHO position paper. J Allergy Clin Immunol. 1998;102:558–62. doi: 10.1016/S0091-6749(98)70271-4. [PubMed] [Cross Ref]
- Lockey RF, Nicoara-Kasti GL, Theodoropoulos DS, Bukantz SC. Systemic reactions and fatalities associated with allergen immunotherapy. Ann Allergy Asthma Immunol. 2001;87:47–55. [PubMed]
- Canonica GW, Passalacqua G. Noninjection routes for immunotherapy. J Allergy Clin Immunol. 2003;111:437–48. doi: 10.1067/mai.2003.129. [PubMed] [Cross Ref]
- Wilson DR, Torres-Lima M, Durham S. Sublingual immunotherapy for allergic rhinitis: systematic review and meta-analysis. Allergy. 2005;60:4–12. doi: 10.1111/j.1398-9995.2005.00699.x. [PubMed] [Cross Ref]
- Shekelle PG, Woolf SH, Eccles M, Grimshaw J. Clinical guidelines: developing guidelines. BMJ. 1999;318:593–96. [PMC free article] [PubMed]
- Wilson D, Torres-Lima M, Durham S. Sublingual immunotherapy for allergic rhinitis. Cochrane Database of Systematic Reviews. 2003. p. CD002893. DOI: 10.1002/14651858.CD002893.
- Sopo SM, Macchiaolo M, Zorzi G, Tripodi S. Sublingual immunotherapy in asthma and rhinoconjunctivitis: systematic review of paediatric literature. Arch Dis Child. 2004;89:620–4. doi: 10.1136/adc.2003.030411. [PMC free article] [PubMed] [Cross Ref]
- Olaguibel JM, Alvarez Puebla MJ. Efficacy of sublingual allergy vaccination for respiratory allergy in children. Conclusions from one meta-analysis. J Investig Allergol Clin Immunol. 2005;15:9–16. [PubMed]
- Penagos M, Compalati E, Tarantini F, Passalacqua G, Canonica GW. Efficacy of sublingual immunotherapy in the treatment of allergic rhinitis in pediatric patients 3 to 18 years of age: a meta-analysis of randomized, placebo-controlled, double-blind trials. Ann Allergy Asthma Immunol. 2006;97:141–8. [PubMed]
- Penagos M, Passalacqua G, Compalati E, Baena-Cagnani CE, Orozco S, Pedroza A, et al. Meta-analysis of the efficacy of sublingual immunotherapy in the treatment of allergic asthma in pediatric patients, 3 to 18 years of age. Chest. 2008;133:599–609. doi: 10.1378/chest.06-1425. [PubMed] [Cross Ref]
- Roder E, Berger MY, de Groot H, van Wiik RG. Immunotherapy in children and adolescents with allergic rhinoconjunctivitis: a systematic review. Pediatr Allergy Immunol. 2008;19:197–207. doi: 10.1111/j.1399-3038.2007.00648.x. [PubMed] [Cross Ref]
- Bufe A, Eberle P, Franke-Beckmann E, Funck J, Kimmig L, Klimek M, et al. Safety and efficacy in children of an SQ-standardized grass allergen tablet for sublingual immunotherapy. J Allergy Clin Immunol. 2009;123:167–73. doi: 10.1016/j.jaci.2008.10.044. [PubMed] [Cross Ref]
- Wahn U, Tabar A, Kuna P, Halken S, Montagut A, de Beaumont O, et al. Efficacy and safety of 5-grass-pollen sublingual immunotherapy tablets in pediatric allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2009;123:160–65. doi: 10.1016/j.jaci.2008.10.009. [PubMed] [Cross Ref]
- Larenas-Linnemann D. Sublingual immunotherapy in children: complete and updated review supporting evidence of efficacy. Curr Opin Allergy Clin Immunol. 2009;9:168–76. doi: 10.1097/ACI.0b013e328329a2a9. [PubMed] [Cross Ref]
- Valovirta E, Jacobsen L, Ljorring C, Koivikko A, Savolainen J. Clinical efficacy and safety of sublingual immunotherapy with tree pollen extract in children. Allergy. 2006;61:1177–83. doi: 10.1111/j.1398-9995.2006.01190.x. [PubMed] [Cross Ref]
- Marcucci F, Sensi L, Di Cara G, Incorvaia C, Frati F. Dose dependence of immunological response to sublingual immunotherapy. Allergy. 2005;60:952–56. doi: 10.1111/j.1398-9995.2005.00786.x. [PubMed] [Cross Ref]
- Novembre E, Galli E, Landi F, Caffarelli C, Pifferi M, De Marco E, et al. Coseasonal sublingual immunotherapy reduces the development of asthma in children with allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2004;114:851–7. doi: 10.1016/j.jaci.2004.07.012. [PubMed] [Cross Ref]
- André C, Vatrinet C, Galvain S, Carat F, Sicard H. Safety of sublingual swallow immunotherapy in children and adults. Int Arch Allergy Immunol. 2000;121:229–234. doi: 10.1159/000024322. [PubMed] [Cross Ref]
- Gidaro GB, Frati F, Sensi L, Incorvaia C, Frati F, Ciprandi G. The safety of sublingual-swallow immunotherapy: an analysis of published studies. Clin Exp Allergy. 2005;35:565–571. doi: 10.1111/j.1365-2222.2005.02240.x. [PubMed] [Cross Ref]
- Passalacqua G, Guerra L, Compalati E, Canonica GW. The safety of allergen specific sublingual immunotherapy. Curr Drug Saf. 2007;2:117–23. doi: 10.2174/157488607780598340. [PubMed] [Cross Ref]
- de Groot H, Bijl A. Anaphylactic reaction after the first dose of sublingual immunotherapy with grass pollen tablet. Allergy. 2009;64:963–4. doi: 10.1111/j.1398-9995.2009.01998.x. [PubMed] [Cross Ref]
- Cochard MM, Eigenmann PA. Sublingual immunotherapy is not always a safe alternative to subcutaneous immunotherapy. J Allergy Clin Immunol. 2009;124:378–9. doi: 10.1016/j.jaci.2009.04.040. [PubMed] [Cross Ref]
- Tripodi S, Di Rienzo Businco A, Benincori N, Scala G, Pingitore G. Safety and tolerability of ultra-rush induction, less than one hour, of sublingual immunotherapy in children. Int Arch Allergy Immunol. 2005;139:149–152. doi: 10.1159/000090391. [PubMed] [Cross Ref]
- Ariano R, Incorvaia C, La Grutta S, Marcucci F, Pajno G, Sensi L, et al. Safety of sublingual immunotherapy started during the pollen season. Curr Med Res Opin. 2009;25:103–7. doi: 10.1185/03007990802591673. [PubMed] [Cross Ref]
- Fiocchi A, Pajno G, La Grutta S, Pezzuto F, Incorvaia C, Sensi L, et al. Safety of SLIT in children aged 3 to 7 years. Ann Allergy Asthma Immunol. 2005;95:254–258. [PubMed]
- Di Rienzo V, Minelli M, Musarra A, Sambugaro R, Pecora S, Canonica GW. Post-marketing survey on the safety of sublingual immunotherapy in children below the age of 5 years. Clin Exp Allergy. 2005;35:560–4. doi: 10.1111/j.1365-2222.2005.02219.x. [PubMed] [Cross Ref]
- Agostinis F, Foglia C, Landi M, Cottini M, Lombardi C, Canonica GW, et al. The safety of sublingual immunotherapy with one or multiple pollen allergens in children. Allergy. 2008;63:1637–9. doi: 10.1111/j.1398-9995.2008.01742.x. [PubMed] [Cross Ref]
- Cadario G, Ciprandi G, Di Cara G, Fadel R, Incorvaia C, Marcucci F, et al. Comparison between continuous or intermittent schedules of sublingual immunotherapy for house dust mites: effects on compliance, patients satisfaction, quality of life and safety. Int J Immunopathol Pharmacol. 2008;21:471–3. [PubMed]
- Haynes RB, Sackett DL, Taylor DW. Compliance in healthcare. Johns Hopkins University Press, Baltimore; 1979.
- Incorvaia C, Mauro M, Ridolo E, Puccinelli P, Liuzzo M, Scurati S, et al. Patient’s compliance with allergen immunotherapy. Patient preference and adherence. 2008;2:247–50.
- Passalacqua G, Musarra A, Pecora S, Amoroso S, Antonicelli L, Cadario G, et al. Quantitative assessment of the compliance with once daily sublingual immunotherapy in children (EASY project: Evaluation of A novel SLIT formulation during a Year) Pediatr Allergy Immunol. 2007;18:56–62. doi: 10.1111/j.1399-3038.2007.00636.x. [PubMed] [Cross Ref]
- Pajno GB, Vita D, Caminiti L, Arrigo T, Lombardo F, Incorvaia C, et al. Children’s compliance with allergen immunotherapy according to administration routes. J Allergy Clin Immunol. 2005;116:1380–81. doi: 10.1016/j.jaci.2005.07.034. [PubMed] [Cross Ref]
- Berto P, Frati F, Incorvaia C. Economic studies of immunotherapy: a review. Curr Opin Allergy Clin Immunol. 2008;8:585–9. doi: 10.1097/ACI.0b013e32831411e9. [PubMed] [Cross Ref]
- Bousquet J, Van Cauwenberge P., (eds) Allergic Rhinits and its Impact on Asthma (ARIA) J Allergy Clin Immunol. 2001;108:S146–S150.
- Berto P, Bassi M, Incorvaia C, Frati F, Puccinelli P, Giaquinto C, et al. Cost effectiveness of sublingual immunotherapy in children with allergic rhinitis and asthma. Eur Ann Allergy Clin Immunol. 2005;37:303–8. [PubMed]
- Omnes LF, Bousquet J, Scheinmann P, Neukirch F, Jasso-Mosqueda G, Chicoye A, et al. Pharmacoeconomic assessment of specific immunotherapy versus current symptomatic treatment for allergic rhinitis and asthma in France. Eur Ann Allergy Clin Immunol. 2007;39:148–56.
- Bousquet J, Scheinmann P, Guinnepain MT, et al. Sublingual-swallow immunotherapy (SLIT) in patients with asthma due to house-dust mites: a double-blind, placebo-controlled study. Allergy. 1999;54(3):249-60
- Purello-D’Ambrosio F, Gangemi S, Isola S, et al. Sublingual immunotherapy: a double-blind, placebo-controlled trial with Parietaria judaica extract standardized in mass units in patients with rhinoconjunctivitis, asthma, or both. Allergy. 1999;54(9):968-73.
- Ippoliti F, De Santis W, Volterrani A, et al. Immunomodulation during sublingual therapy in allergic children. Pediatr Allergy Immunol. 2003;14(3):216-21.
- Passalacqua G, Canonica GW. Long lasting efficacy of specific immunotherapy. Allergy 2002;57:275-6
- Di Rienzo V, Marcucci F, Puccinelli P, et al. Long-lasting effect of sublingual immunotherapy in children with asthma due to house dust mite: a 10-year prospective study. Clin Exp Allergy. 2003;33(2):206-10
- Canonica GW, Compalati E, Fumagalli F, et al. Sublingual and oral immunotherapy. Immunol Allergy Clin North Am. 2004;24(4):685-704
- Di Rienzo V, Pagani A, Parmiani S, et al. Post-marketing surveillance study on the safety of sublingual immunotherapy in pediatric patients. Allergy. 1999;54(10):1110-3.
- Moller C, Dreborg S, Ferdousi HA, et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J Allergy Clin Immunol. 2002;109(2):251-6.
- Marogna M, Spadolini I, Massolo A, et al. Randomized controlled open study of sublingual immunotherapy for respiratory allergy in real-life: clinical efficacy and more. Allergy 2004;59(11):1205-10.
- Hemmings, WA. Antigen absorption by the gut. Lancaster, England: MTP Press; 1978.
- Elson, CO, Heck, JA, Strober, W. T-cell regulation of murine IgA synthesis. J Exp Med 1979; 149:632.
- Frew, AJ. How does sublingual immunotherapy work?. J Allergy Clin Immunol 2007; 120:533.
- La Rosa, M, Ranno, C, Andre, C, et al. Double-blind placebo-controlled evaluation of sublingual-swallow immunotherapy with standardized Parietaria judaica extract in children with allergic rhinoconjunctivitis. J Allergy Clin Immunol 1999; 104:425.
- Lima, MT, Wilson, D, Pitkin, L, et al. Grass pollen sublingual immunotherapy for seasonal rhinoconjunctivitis: a randomized controlled trial. Clin Exp Allergy 2002; 32:507.
- Tari, MG, Mancino, M, Monti, G. Efficacy of sublingual immunotherapy in patients with rhinitis and asthma due to house dust mite. A double-blind study. Allergol Immunopathol (Madr) 1990; 18:277.
- Bufe, A, Ziegler-Kirbach, E, Stoeckmann, E, et al. Efficacy of sublingual swallow immunotherapy in children with severe grass pollen allergic symptoms: a double-blind placebo-controlled study. Allergy 2004; 59:498.
- Smith, H, White, P, Annila, I, et al. Randomized controlled trial of high-dose sublingual immunotherapy to treat seasonal allergic rhinitis. J Allergy Clin Immunol 2004; 114:831.
- Durham, SR, Yang, WH, Pedersen, MR, et al. Sublingual immunotherapy with once-daily grass allergen tablets: a randomized controlled trial in seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol 2006; 117:802
- Bahceciler, NN, Isik, U, Barlan, IB, Basaran, MM. Efficacy of sublingual immunotherapy in children with asthma and rhinitis: a double-blind, placebo-controlled study. Pediatr Pulmonol 2001; 32:49.
- Calderon, M, Essendrop, M. Specific immunotherapy with high dose SO standardized grass allergen tablets was safe and well tolerated. J Investig Allergol Clin Immunol 2006; 16:338.
- Ciprandi, G, Cirillo, I, Fenoglio, D, et al. Sublingual immunotherapy induces spirometric improvement associated with IL-10 production: preliminary reports. Int Immunopharmacol 2006; 6:1370.
- Arikan, C, Bahceciler, NN, Deniz, G, et al. Bacillus Calmette-Guerin-induced interleukin-12 did not additionally improve clinical and immunologic parameters in asthmatic children treated with sublingual immunotherapy. Clin Exp Allergy 2004; 34:3.
- Ippoliti, F, De Santis, W, Volterrani, A, et al. Immunomodulation during sublingual therapy in allergic children. Pediatr Allergy Immunol 2003; 14:216.
- Passalacqua, G, Canonica, GW. Sublingual or injection immunotherapy: the final answer?. Allergy 2004; 59:37.
- Bahceciler, NN, Ozdemir, C, Barlan, IB. Immunologic aspects of sublingual immunotherapy in the treatment of allergy and asthma. Curr Med Chem 2007; 14:265.
- Wilson, DR, Torres, LI, Durham, SR. Sublingual immunotherapy for allergic rhinitis. Cochrane Database Syst Rev 2003; :CD002893.
- Kleine-Tebbe, J, Ribel, M, Herold, DA. Safety of a SQ-standardised grass allergen tablet for sublingual immunotherapy: a randomized, placebo-controlled trial. Allergy 2006; 61:181.
- Larsen, TH, Poulsen, LK, Melac, M, et al. Safety and tolerability of grass pollen tablets in sublingual immunotherapy–a phase-1 study. Allergy 2006; 61:1173.
- Dahl, R, Kapp, A, Colombo, G, et al. Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol 2006; 118:434.
- Press release may be acccessed at http://www.forbes.com/feeds/afx/2007/11/16/afx4348325.html.
- Blaiss, M, Maloney, J, Nolte, H, et al. Efficacy and Safety of Grass Allergy Immunotherapy Tablet (AIT) in a North American Pediatric Population. J Allergy Clin Immunol 2010; 125:. (in press)(Abstract).
- Didier, A, Malling, HJ, Worm, M, et al. Optimal dose, efficacy, and safety of once-daily sublingual immunotherapy with a 5-grass pollen tablet for seasonal allergic rhinitis. J Allergy Clin Immunol 2007; 120:1338.
- Wahn, U, Tabar, A, Kuna, P, et al. Efficacy and safety of 5-grass-pollen sublingual immunotherapy tablets in pediatric allergic rhinoconjunctivitis. J Allergy Clin Immunol 2009; 123:160.
- Dahl, R, Kapp, A, Colombo, G, et al. Sublingual grass allergen tablet immunotherapy provides sustained clinical benefit with progressive immunologic changes over 2 years. J Allergy Clin Immunol 2008; 121:512.
- Durham, SR, Emminger, W, Kapp, A, et al. Long-term clinical efficacy in grass pollen-induced rhinoconjunctivitis after treatment with SQ-standardized grass allergy immunotherapy tablet. J Allergy Clin Immunol 2010; 125:131.
- Allergy 2010; 65:753.
- Esch, RE, Bush, RK, Peden, D, Lockey, RF. Sublingual-oral administration of standardized allergenic extracts: phase 1 safety and dosing results. Ann Allergy Asthma Immunol 2008; 100:475.
- Skoner, D, Gentile, D, Busg, RK, et al. Sublingual Immuntherapy in Patients with Allergic Rhinoconjunctivitis Caused By Ragweed Pollen. J Allergy Clin Immunol 2010; 125:. (in press)(Abstract).
- Press release viewable at http://www.greerlabs.com/research_dev/rdev.slit.updates.php.
- Bush RK, Swenson C, Fahlberg B, et al. High-dose House Dust Mite Sublingual Immunotherapy Increased Antigen-specific Serum IgG4 and PD20 to HDM Antigen. J Allergy Clin Immunol 2009; 123:725. (Abstract).
- Reshamwala, SJ, Song, GP, Yu, R, et al: Study of Sublingual Immuntherapy in Subjects with Dermatophagoides Farinae and Timothy Grass Allergy. J Allergy Clin Immunol 2009; 123:S126. (Abstract).
- Amar, SM, Harbeck, RJ, Sills, M, et al. Response to sublingual immunotherapy with grass pollen extract: monotherapy versus combination in a multiallergen extract. J Allergy Clin Immunol 2009; 124:150.
- Creticos, PS, Balcer-Whaley, SL, Moldt, P, Pedersen, O. Safety and Efficacy of Oral Immunotherapy with a Microencapsulated Ragweed Pollen Extract (MRPE) in Patients with Ragweed-induced Seasonal Allergic Rhinitis. Presented at 27th Symposium of Collegium Internationale Allergologicum in Curacao, May 2008. (Abstract).
- Creticos PS, Balcer-Whaley, SL, Moldt, P, Pedersen, O. Comparison of Compositional Differences and Relative Potency Between Different Manufacturers of Ragweed Pollen Extracts. J Allergy Clin Immunol 2007;119:S57. (Abstract).
- Dahl, R, Stender, A, Rak, S. Specific immunotherapy with SQ standardized grass allergen tablets in asthmatics with rhinoconjunctivitis. Allergy 2006; 61:185.
- Bufe, A, Eberle, P, Franke-Beckmann, E, et al. Safety and efficacy in children of an SQ-standardized grass allergen tablet for sublingual immunotherapy. J Allergy Clin Immunol 2009; 123:167.
- Passalacqua, G, Guerra, L, Compalati, E, Canonica, GW. The safety of allergen specific sublingual immunotherapy. Curr Drug Saf 2007; 2:117.
- Rodriguez-Perez, N, Ambriz-Moreno Mde, J, Canonica, GW, Penagos, M. Frequency of acute systemic reactions in patients with allergic rhinitis and asthma treated with sublingual immunotherapy. Ann Allergy Asthma Immunol 2008; 101:304.
- de Groot, H, Bijl, A. Anaphylactic reaction after the first dose of sublingual immunotherapy with grass pollen tablet. Allergy 2009; 64:963.
- Cox, LS, Linnemann, DL, Nolte, H, et al. Sublingual immunotherapy: a comprehensive review. J Allergy Clin Immunol 2006; 117:1021.
- Casale, TB, Canonica, GW, Bousquet, J, et al. Recommendations for appropriate sublingual immunotherapy clinical trials. J Allergy Clin Immunol 2009; 124:665.
- Khinchi, MS, Poulsen, LK, Carat, F, et al. Clinical efficacy of sublingual and subcutaneous birch pollen allergen-specific immunotherapy: a randomized, placebo-controlled, double-blind, double-dummy study. Allergy 2004; 59:45.
- Cox L, Sublingual immunotherapy and allergic rhinitis. Curr Allergy Asthma Rep. 2008 Apr;8(2):102-10.
- Cox L. Sublingual immunotherapy in pediatric allergic rhinitis and asthma: efficacy, safety and practical considerations. Curr Allergy Asthma Rep 2007 Nov;7(6):410-20.
- Cox LS, Linnemann DL, Nolte H, Weldon D, Finegold I, Nelson HS. Sublingual immunotherapy: A comprehensive review. J Allergy Clin Immunol 2006. May;117(5):1021-1035.
- Passalacqua G, Durham SR in cooperation with the Global Allergy and Asthma European Network. Allergic Rhinitis and its Impact on Asthma update: Allergen Immunotherapy. J Allergy Clin Immunol 2007 April;119(4):881-891.
- Smith, H, White P, Annila I, Poole J, Andre C, Frew A. Randomized controlled trail of high-dose sublingual immunotherapy to treat seasonal allergic rhinitis. J Allergy Clin Immunol 2004. 114(4);831-837.
- Wilson DR, Lima MT, Durham SR. Sublingual immunotherapy for allergic rhinitis: systematic review and met-analysis*. Allergy 2005;60:4-12.
- Roder, E, Berger, MY, Hop, WC, et al. Sublingual immunotherapy with grass pollen is not effective in symptomatic youngsters in primary care. J Allergy Clin Immunol 2007; 119:892.
- Gidaro G, Marcucci F, Sensi L, Incorvaia C, Frati F, Ciprandi G (2005). “The safety of sublingual-swallow immunotherapy: an analysis of published studies”. Clin Exp Allergy 35 (5): 565–71.
- Kagi MK, Wüthrich B. Different methods of local allergen-specific immunotherapy. Allergy 2000;257:379-88. [PubMed]
- Bousquet J, Lockey RF, Malling HJ. WHO position paper. Allergen immunotherapy: therapeutic vaccines for allergic disease. Allergy 1998;53(Suppl):1-42.
Bagnasco M, Passalacqua G, Villa G Augeri C, Flamigni G, Borini E, et al. Pharmacokinetics of an allergen and a monomeric allergoid for oromucosal immunotherapy in allergic volunteers. Clin Exp Allergy 2001;31:54-60. [PubMed]
Brown JL, Frew AJ. The efficacy of oromucosal immunotherapy in respiratory allergy. Clin Exp Allergy 2001;31:8-10. [PubMed]
Malling HJ. Sublingual immunotherapy. Clin Exp Allergy 1996;26:1228-31. [PubMed]
Mestecky J. The common mucosal immune system and current strategies for induction of immune responses in external secretions. J Clin Immunol 1987;7:265-76. [PubMed]
Canonica GW, Passalacqua G. Noninjection routes for immunotherapy. J Allergy Clin Immunol 2003;111:437-48. [PubMed]
Tari MG, Mancino M, Monti G. Efficacy of sublingual immunotherapy in patients with rhinitis and asthma due to house dust mite: A double-blind study. Allergol Immunopathol 1990;18:277-84. [PubMed]
Hadley JA. Evaluation and management of allergic rhinitis. Med Clin North Am 1999;83:13-25. [PubMed]
Bousquet J, Scheinmann P, Guinnepain MT, Perrin-Fayolle M, Sauvaget J, Tonnel AB, et al. Sublingual-swallow immunotherapy (SLIT) in patients with asthma due to house-dust mites: a double-blind, placebo-controlled study. Allergy 1994;54:249-60. [PubMed]
Taudorf E. Oral immunotherapy of adults with allergic rhinoconjunctivitis. Dan Med Bull 1992;39:542-60. [PubMed]
Fanta C, Bohle B, Hirt W, Siemann U, Horak F, Kraft D, et al. Systemic immunological changes induced by administration of grass pollen allergens via the oral mucosa during sublingual immunotherapy. Int Arch Allergy Immunol 1999;120:218-24. [PubMed]
Quirino T, Iemoli E, Siciliani E, Parmiani S, Milazzo F. Sublingual versus injective immunotherapy in grass pollen allergic patients: A double blind (double dummy) study. Clin Exp Allergy 1996;26:1253-61. [PubMed]
Frew AJ, Smith HE. Sublingual immunotherapy. J Allergy Clin Immunol 2001;107:441-4. [PubMed]
Gozalo F, Martin S, Rico P, Alvarez E, Cortes C. Clinical efficacy and tolerance of two year Lolium perenne sublingual immunotherapy. Allergol Immunopathol 1997;25:219-27. [PubMed]
Lima MT, Wilson D, Pitkin A, Roberts A, Nouri-Aria K, Jacobson M, et al. Grass pollen sublingual immunotherapy for seasonal rhinoconjunctivitis: A randomized controlled trial. Clin Exp Allergy 2002;32:507-14. [PubMed]
- Dunsky EH; Goldstein, MF; Dvorin, DJ; Belecanech, GA (2006). “Anaphylaxis to sublingual immunotherapy”. Allergy 61 (10): 1235.
- Moingeon P, Batard T, Fadel R, Frati F, Sieber J, Van Overtvelt L (2006). “Immune mechanisms of allergen-specific sublingual immunotherapy”. Allergy 61 (2): 151–65.
- NOON L (1953). “Prophylactic inoculation against hay fever”. Int Arch Allergy Appl Immunol 4 (4): 285–8.
- Curtis HH. (1900) The immunizing cure of hayfever. Med News (NY);77:16-8.
- Black JH. (1927) The oral administration of pollen. J Lab Clin Med;12:1156
- Morris D (1969). “Use of sublingual antigen in diagnosis and treatment of food allergy”. Ann Allergy 27 (6): 289–94.
- Morris D (1970). “Treatment of respiratory disease with ultra-small doses of antigens”. Ann Allergy 28 (10): 494–500.
- Reid M, Lockey R, Turkeltaub P, Platts-Mills T (1993). “Survey of fatalities from skin testing and immunotherapy 1985-1989″. J Allergy Clin Immunol 92 (1 Pt 1): 6–15.
- Bousquet J, Lockey R, Malling H (1998). “Allergen immunotherapy: therapeutic vaccines for allergic diseases. A WHO position paper”. J Allergy Clin Immunol 102 (4 Pt 1): 558–62.
- Canonica G, Passalacqua G (2003). “Noninjection routes for immunotherapy”. J Allergy Clin Immunol 111 (3): 437–48; quiz 449.
- Medicare National Coverage Determinations Manual; Chapter 1, Part 2 (Sections 90 – 160.25), Page 14. Coverage Determinations (Rev. 45, 12-06-05)110.9 – Antigens Prepared for Sublingual Administration (Rev. 1, 10-03-03)CIM 45-28
- Rodriguez-Perez, et al. Frequency of acute systemic reactions in patients with allergic rhinitis and asthma treated with sublingual immunotherapy. Annals of Allergy, Asthma and Immunology 2008; 101:304-310
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