30.2.1 Why Immunotherapy? Why Sublingual Immunotherapy?

Classic treatment for allergic disease includes avoidance of allergens and/or environmental control measures, pharmacotherapy, and IT. Immunotherapy is the only treatment approach capable of altering the underlying immunopathology of allergy, wherein gradual changes in the body’s immune system occur (i.e., shift away from T helper [T_h2] responses, increase in T-regulatory response) such that exposure to the allergen does not elicit substantial clinical symptoms. Immunotherapy can yield long-term symptom reduction even after discontinuing therapy and, in some studies, has been shown to reduce the progression of allergic disease to asthma, as well as the development of new allergen sensitizations. It can reduce a patient’s long-term medication requirements and overall health care costs over time.

SCIT has been the predominant method of IT in the United States since it was introduced around 100 years ago. There are certain risks associated with injection IT, such as anaphylactic reactions, that make alternative approaches of IT delivery attractive. In addition, although very rare, deaths have resulted from SCIT administration. Various alternative methods of allergen IT have been proposed and utilized throughout the years. These include oral IT (swallowing allergen for action/absorption in the gut), bronchial inhalation of allergen, nasal routes of allergen administration, and intraocular IT. However, due to marginal benefit or the provocation of substantial and uncomfortable side effects, these IT methods are not commonly used.

Sublingual immunotherapy is the one alternative IT modality that has been widely adopted throughout the world. It differs from oral IT by holding the antigen under the tongue for a period of time before either spitting it out, or more commonly, swallowing the antigen. The SLIT technique was first introduced in the United States in the 1940s; however, it did not gain widespread use at that time. In recent decades, SLIT administration has substantially increased in the United States.

30.2.2 How Does SLIT Work?

There are dendritic cells in the sublingual mucosa, which are antigen-presenting cells. Allergens contained in the SLIT preparation are taken up directly in the sublingual region. This is why it is important to keep the SLIT aqueous solution or tablet held under the tongue for the requisite amount of time, often 2 minutes. The antigen travels to the lymph node within 12 to 24 hours and is processed in a similar fashion to SCIT. Given frequent exposure to food preparations, medications, etc., it is thought that the immunologic mechanisms of the sublingual mucosa may demonstrate increased tolerance compared to the skin and subcutaneous tissue. This may be one reason for the increased safety profile seen with SLIT. For those interested in the specifics—immune suppressive mediators such as interleukin (IL)-10, transforming growth factor (TGF)-beta, and interferon are constitutively produced in the oral mucosa. Also, the oral tissues contain a relatively low number of proinflammatory cells such as eosinophils and macrophages.

30.2.3 What Evidence Do We Have for SLIT Efficacy?

In the mid-1980s, the first “modern” studies of SLIT were reported. Since that time, numerous investigators, mostly from European centers, have described the clinical efficacy and basic science of SLIT. In 1998, the World Health Organization reported that there was sufficient efficacy and safety data available to conclude that SLIT was an acceptable means of IT administration. A subsequent publication by the European Academy of Allergy and Clinical Immunology, as well as the Allergic Rhinitis and its Impact on Asthma (ARIA) document agreed with the utility of SLIT in adults and children.

Presently, in adults, SLIT is considered moderately efficacious for the treatment of allergic rhinitis/rhinoconjunctivitis when compared to placebo, based on several systematic reviews and meta-analyses. With longer treatment, SLIT is considered highly efficacious. In clinical trials, the benefit of SLIT is seen over and above symptom benefit obtained from the use of rescue medications. For children, the strength of SLIT evidence appears to vary by allergen, based on current data. The efficacy of grass pollen SLIT in children is supported by strong evidence, while there is moderate-to-low quality evidence to support house dust mite SLIT in children at the present time.

There are very few head-to-head studies of SLIT versus SCIT, and in most of these, the sample size is small. Meta-analyses-based indirect comparisons of SLIT and SCIT have been performed recently, with some publications reporting that SCIT is more efficacious than SLIT, although this evidence is considered weak at this time.

There have been some investigations into the efficacy of SLIT in preventing the development of asthma and new allergen sensitizations. Although the results of some trials are promising, the strength of evidence is considered to be relatively low overall. Additional investigation into the “preventative effects” of SLIT would be helpful to improve the overall understanding of SLIT efficacy.

30.2.4 SLIT Is Safer Than SCIT. True or False?

Sublingual immunotherapy is generally considered safer than SCIT. This improved safety profile allows for home administration of SLIT, which is more convenient for patients. For patients who are not able to make regular clinic visits for injections, home administration makes IT feasible.

In order to fully understand the safety profile of SLIT, it is best to compare it to SCIT. In a recent survey report of the American Academy of Allergy, Asthma and Immunology and the American College of Allergy, Asthma, and Immunology between 2008 and 2013, 28.9 million injection visits were analyzed. There was a systemic reaction rate of 0.1% of injection visits, with grade 4 systemic reactions reported at 0.1 per 10,000 injections. There were two fatalities that occurred during SCIT under the care of allergists and two fatalities that occurred under the care of non-allergists. While anaphylaxis and deaths have been reported with SCIT, it is important to note that the rate of serious events is very low, and with proper screening and precautions in place, SCIT is a very safe form of IT.

The first report of anaphylaxis with SLIT was published in 2006, and since that time, there have been several case reports that followed. In 2012, an analysis of the rate of anaphylaxis during SLIT was published, noting one case of anaphylaxis per 100 million SLIT doses, or one case of anaphylaxis per 526,000 SLIT treatment years. This is exceptionally low. To authors’ knowledge, there have been no deaths reported with SLIT. Based upon the published rates of systemic reaction and anaphylaxis, SLIT is generally accepted as having a higher safety profile than SCIT.

30.2.5 What Is the Best Dose of SLIT to Give to Patients?

The optimal dosage, timing of administration, and optimal length of treatment with SLIT are not clearly defined. The majority of modern dosing information available in the literature comes from European studies utilizing antigens that are not available in the United States. It is difficult to directly translate the antigen content of sublingual preparations utilized in the majority of the published European studies into dosing with United States allergens. Therefore, it can be difficult to establish the effective dose of SLIT utilizing the liquid-based antigen preparations available in the United States. However, one fairly consistent finding is that higher doses of antigen are generally necessary for SLIT compared to SCIT. It is also clear that SLIT is safe over a wide dosing range.

In 2015, Leatherman and colleagues thoroughly examined the available literature with regard to SLIT dosing. Evidence available at that time revealed that SLIT dosing ranges (in µg/day) could be recommended for Dermatophagoides pteronyssinus , D. farinae, timothy grass, Bermuda grass, ragweed, and “other” pollen. At that time, all other allergens did not have sufficient evidence to recommend SLIT dose ranges. In order to aid the practitioner, some recommended ranges of allergen concentrates to add to aqueous SLIT vials were given. This is a helpful guide to understand the current evidence on SLIT dosing.

The appropriate timing and duration of SLIT have not been defined. In various clinical trials, the antigen has been delivered perennially, preseasonal/coseasonal, as well as coseasonal alone. It is generally accepted that perennial administration of SCIT for 3 to 5 years is preferable to achieve long-term maintenance of the improvement after IT has been completed. For SLIT, however, benefit has been shown with perennial administration, variations of preseasonal/coseasonal administration, and even alternating (months on/months off) administration. Thus, there may be multiple options available for SLIT dosing that can be tailored to the needs of individual patients. These different treatment options will have to be clarified by future trials.