Posted by: Indonesian Children | September 5, 2010

Sublingual Immunotherapy for Children Allergic Diseases

Sublingual Immunotherapy for Children Allergic Diseases

Widodo Judarwanto

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.

Introduction

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 

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. 

Mechanism  

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. 

History

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.

Benefits

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. 

Side Effects

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. 

 

Procedure 

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

All systematic revisions and meta-analysis found that the most common adverse events to SLIT, regardless the age, are local reactions in the oropharynx – with itching, tingling and swelling in the mouth – followed by local gastrointestinal reactions – with nausea, vomiting or diarrhea – and that systemic reactions such as asthma, rhinitis, or urticaria, are quite rare. An increased risk of systemic reactions is apparent in subjects undergoing SLIT because of previous systemic reactions to SCIT. In particular, one of the cases of anaphylaxis concerned a pediatric patient, who had had urticaria to previous SCIT treatment and developed an anaphylactic reaction after the very first dose of a grass pollen tablet formulation with no updosing phase .
Some studies addressed specific safety issues in children. SLIT was well tolerated using ultra-rush schedules – that reach the maintenance dose in a few hours  – and also starting the treatment during the pollen season [24]. Two studies demonstrated that SLIT is safe also in children younger than 5 years (that is the age limit indicated for SCIT), as assessed by comparable rate and kind of adverse effects in patients aged less or more than 5 years. A further observation regarded children treated with one or multiple allergen extracts, who showed comparable rates of side effects, more than 90% being mild and self-resolving . Concerning SLIT with house dust mites extracts, a recent study (including both adults and children) reported a comparable safety and tolerability in patients treated continuously or intermittently, i.e. 2-month treatment alternate to-2 month suspension.

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

The clinically efficacy of SLIT, as of SIT in general, is evaluated by the decrease in symptom scores of rhinitis and asthma and in consumption of symptomatic drugs. Many placebo-controlled studies are conducted on small patient populations and cannot achieve a reliable statistical significance, but their combined evaluation by the tool of meta-analysis is considered an adequate method to obtain more robust data . The results obtained by the Cochrane Collaboration method  are expressed as standardized mean difference (SMD) and allow to compare the effect of SLIT on actively and placebo treated patients. Also systematic reviews, that is, literature analysis without using the Cochrane method, are available.
The progressive increase in number of SLIT studies addressing the pediatric population made possible to perform specific meta-analyses and systematic reviews. The first systematic review included the studies up to June 2003, which were evaluated qualitatively, and concluded for low to moderate efficacy of SLIT only in children with house dust mite induced mild to moderate asthma . A meta-analysis by Olaguibel et al including 7 randomized controlled studies conducted on children aged up to 14 years was substantially in agreement, since it found that SLIT was significantly effective on asthma symptoms (SMD -1.42, p = 0.01) and on drug consumption (SMD -1.01, p = 0.06), while the improvement did not reach the significance for nasal and conjunctival symptoms .
A further meta-analysis on SLIT in children was published in 2006 : in this case the evaluation concerned the efficacy on allergic rhinitis including 10 randomized controlled studies, with an overall number of 484 patients (245 actively and 239 placebo treated). A significant reduction of both symptoms (SMD – 0.56, p = 0.02) and medication (- 0.76, p = 0.03) was observed. A notable aspect was provided from the sub-analysis addressing the length of treatment and the kind of allergen administered, which demonstrated a higher efficacy for durations longer than 18 months and for pollen allergens compared to house dust mites.
The same group performed a meta-analysis on the efficacy of SLIT in allergic asthma, analyzing 9 studies on pediatric patients which included a total number of 441 patients, 232 actively treated and 209 placebo-treated. A significant reduction was found in both symptoms scores (SMD – 1.14, p = 0.02) and drug use (SMD -1.63, p = 0.007).
A systematic review in the same year by Roder et al evaluating any form of immunotherapy in children concluded for no evidence of effectiveness in the subgroup of 11 studies on SLIT, but the review was based on analysis of each single study and not on pooling all data together. The authors justified such approach with the relevant heterogeneity of the available studies.
Actually, heterogeneity, which is mainly due to different scoring systems in the various studies. is a limit of meta-analysis. However, a data source alternative to meta-analysis are studies conducted on large numbers of patients that provide adequate statistical power. The recent preparations for SLIT in orosoluble tablet of grass pollen extract were evaluated on large populations, including 253 children treated by a one grass (Phleum pratense) extract, and 278 children treated with a 5-grass pollen extract . These studies showed a highly significant improvement in symptom and rescue medications scores in actively treated compared with placebo treated patients during the grass pollen season. Thus, the criticism on the efficacy of SLIT in children does not seem to have ground. An updated and balanced review on this issue by Larenas-Linnemann was recently published. The author after accurate analysis of all the available studies concluded that “evidence of effect is confirmed for SLIT in children with allergic rhinitis or asthma caused by pollen exposure”, while there is yet room for investigations on long-term effects and preventive action of SLIT, as well as on optimal dosing for dust mites. Indeed, the dosing is a pivotal factor, and the dose-dependence of efficacy in children treated with pollen extract was clearly demonstrated both clinically  and immunologically . Dose-response studies in mite allergic children are warranted. Another important observation concerns the capacity of SLIT to prevent the development of asthma in children with seasonal rhinitis treated with grass pollen extract compared with subjects treated with standard symptomatic drugs

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

Compliance to SLIT
According to established definitions, compliance is “The extent to which a patient’s behavior matches the prescriber’s advice” and adherence is “The extent to which the patient’s behavior matches agreed recommendations from the prescriber”, and both of them are essential for the clinical outcome of a medical treatment. A number of studies conducted on SCIT showed that the major cause of noncompliance was the inconvenience, related to injections and particularly to their frequency, and the cost of the treatment. SLIT has different compliance issues than SCIT, because it is administered at home by patients themselves and thus it is not affected by most causes reported for non-compliance to allergen injections, having instead compliance problems similar to drug treatment. Some studies not specifically designed for compliance (for instance safety and tolerability analyses) reported that treatment withdrawal is frequently caused by repeated local reactions in the mouth or at gastrointestinal level. Concerning specific compliance and adherence studies, the available data indicate quite satisfactory results.
In a study on children treated with SLIT by an allergen extract in monodoses, parents were interviewed by unscheduled phone calls at the third and sixth month of SLIT and asked to count at once the remaining doses; a compliance rate higher than 75% was found in 85% of children at the third month and in 84% of children at the sixth month; the major cause of withdrawal (5.6% of cases) was the cost of treatment, while side effects accounted for 1.4% of stopping. In a study comparing compliance to SLIT, SCIT and local nasal immunotherapy in children, data on SLIT concerned 806 patients, 173 of whom (21.4%) were noncompliant, with a highly significant difference (p < 0.0001) for a better compliance in hospital setting (90.5%) compared to private office setting (61.2%); the most common reason of withdrawal was the cost of treatment, reported globally in 36.4% of cases, followed by inconvenience, feeling of inefficacy, and side effects.
Cost-effectiveness of SLIT
Many studies are available, recently reviewed, showing that SLIT provides economic advantage compared with drug treatment by bringing a better clinical outcome at a reduced cost or an extra benefit at a very acceptable extra cost. Concerning children, fhe first published study dealt with the evaluation of cost effectiveness of SLIT, with the high dose suggested in the ARIA document, in subjects with allergic rhinitis and asthma. From records of pediatric patients seen for respiratory allergy, who had 1-year data prior to receive SLIT and 3-year data on high dose SLIT, outcome measures (the number of exacerbations, visits, absence from nursery or school) were analyzed. Moreover, direct costs (Euro spent on drugs, specialists visits, and SLIT) and indirect costs (costs resulting from children school and parental work loss) were considered. A second analysis compared a sub-group of children with allergic asthma, using a control group for costs, based on records of patients not treated with SLIT, extracted from a network-database of pediatricians. An overall number of 135 children were analyzed, 46 with perennial and 89 with seasonal allergy, with comparable gender and age distribution. A substantial reduction was found in all outcome measures during SLIT compared with the previous period. The average annual cost/patient was Euro 2672 before SLIT initiation and Euro 629/year during SLIT. Similar results were found for allergen subgroups. The asthma analysis involved 41 children with SLIT and 35 controls, and also showed a substantial reduction in outcomes, though the direct cost per patient over the 4 years follow-up was € 1182 for SLIT-treated children and € 1100 for controls . A study conducted in France estimated that in children treated with SLIT for house dust mite or pollen allergies, the incremental costs per asthma case avoided over a 7-year period, compared with standard symptomatic treatment, were 3938 Euro for dust mite and 824 Euro for pollen allergy; of note, there was an economic advantage of SLIT also versus SCIT for pollen allergy, since the incremental cost for the latter was 1708 Euro

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.

Summary 

  • 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.

 

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Responses

  1. Dear Dr Widodo,
    Are you able to supply SLIT to your patient in Indonesia?

    Thanks


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