Sublingual immunotherapy
Encyclopedia
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.
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.
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 cell
s which interact with T lymphocytes (T-cells).
Sublingual immunotherapy takes advantage of each individuals ability to develop immunologic tolerance
to non-pathogenic antigen
s 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 cell
s 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.
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 trial
s 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."
For more information on the current status of SLIT in the US visit AAAAI.ORG or ACAAI.ORG.
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.
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.
Allergy
An Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment. A substance that causes a reaction is called an allergen. These reactions are acquired, predictable, and rapid...
treatment that uses an allergen
Allergen
An allergen is any substance that can cause an allergy. In technical terms, an allergen is a non-parasitic antigen capable of stimulating a type-I hypersensitivity reaction in atopic individuals....
solution given under the tongue
Tongue
The tongue is a muscular hydrostat on the floors of the mouths of most vertebrates which manipulates food for mastication. It is the primary organ of taste , as much of the upper surface of the tongue is covered in papillae and taste buds. It is sensitive and kept moist by saliva, and is richly...
, 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.
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
Eczema
Eczema is a form of dermatitis, or inflammation of the epidermis . In England, an estimated 5.7 million or about one in every nine people have been diagnosed with the disease by a clinician at some point in their lives.The term eczema is broadly applied to a range of persistent skin conditions...
in young children and progress through allergic rhinitis
Allergic rhinitis
Allergic rhinitis, also known as pollenosis or hay fever, is an allergic inflammation of the nasal airways.It occurs when an allergen, such as pollen, dust or animal dander is inhaled by an individual with a sensitized immune system...
and asthma
Asthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
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 systemImmune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
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 cell
Dendritic cell
Dendritic cells are immune cells forming part of the mammalian immune system. Their main function is to process antigen material and present it on the surface to other cells of the immune system. That is, dendritic cells function as antigen-presenting cells...
s which interact with T lymphocytes (T-cells).
Sublingual immunotherapy takes advantage of each individuals ability to develop immunologic tolerance
Immune tolerance
Immune tolerance or immunological tolerance is the process by which the immune system does not attack an antigen. It can be either 'natural' or 'self tolerance', in which the body does not mount an immune response to self antigens, or 'induced tolerance', in which tolerance to external antigens can...
to non-pathogenic antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
s 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
Cervical lymph nodes
Cervical lymph nodes are lymph nodes found in the neck.-Classification:There are approximately 300 lymph nodes in the neck, and they can be classified in many different ways.Henri Rouvière produced an influential classification in 1938...
. This system modulates the allergic response by creating immune tolerance to antigens. The sublingual mucosa also has pro-inflammatory
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
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
Interleukin 10
Interleukin-10 , also known as human cytokine synthesis inhibitory factor , is an anti-inflammatory cytokine. In humans IL-10 is encoded by the IL10 gene....
(IL-10) which induces regulatory T cell
Regulatory T cell
Regulatory T cells , sometimes known as suppressor T cells, are a specialized subpopulation of T cells which suppresses activation of the immune system and thereby maintains tolerance to self-antigens. The existence of regulatory T cells was the subject of significant controversy among...
s 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
Specific immunotherapy has been practiced for almost 100 years. Classical immunotherapyImmunotherapy
Immunotherapy is a medical term defined as the "treatment of disease by inducing, enhancing, or suppressing an immune response". Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies. While immunotherapies that reduce or suppress are...
by subcutaneous injection
Subcutaneous injection
A subcutaneous injection is administered as a bolus into the subcutis, the layer of skin directly below the dermis and epidermis, collectively referred to as the...
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
Pollen
Pollen is a fine to coarse powder containing the microgametophytes of seed plants, which produce the male gametes . Pollen grains have a hard coat that protects the sperm cells during the process of their movement from the stamens to the pistil of flowering plants or from the male cone to the...
, pet dander
Dander
Dander is an informal term for a material shed from the body of various animals, similar to dandruff. It may contain scales of dried skin and hair, or feathers. It is a cause of allergies in humans....
and mold
Mold
Molds are fungi that grow in the form of multicellular filaments called hyphae. Molds are not considered to be microbes but microscopic fungi that grow as single cells called yeasts...
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
Anaphylaxis
Anaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death". It typically results in a number of symptoms including throat swelling, an itchy rash, and low blood pressure...
. 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
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
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 trial
Randomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...
s 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."
For more information on the current status of SLIT in the US visit AAAAI.ORG or ACAAI.ORG.
Comparison to other allergy management 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
Prednisone
Prednisone is a synthetic corticosteroid drug that is particularly effective as an immunosuppressant drug. It is used to treat certain inflammatory diseases and some types of cancer, but has significant adverse effects...
. 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
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
Atopy
Atopy or atopic syndrome is a predisposition toward developing certain allergic hypersensitivity reactions.Atopy may have a hereditary component, although contact with the allergen must occur before the hypersensitivity reaction can develop ....
, 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.