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.[1]
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.[2]
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.
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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.[3] 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.
Specific immunotherapy has been practiced for almost 100 years. Classical immunotherapy by subcutaneous injection was demonstrated by Noon[4] and Freeman in 1911. The oral route of immunotherapy was suggested earlier in 1900 [5]. Clinical attempts to determine the best dose and route for allergy therapy increased dramatically in the 1920s and 1930s.[6] 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[7]. 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.[8] 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[9]. 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.[10] 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.[11]
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."[12]
For more information on the current status of SLIT in the US visit AAAAI.ORG or ACAAI.ORG.
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.
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 through 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.[13]