Allergen immunotherapy (also termed hyposensitization therapy, immunologic desensitization or allergen-specific immunotherapy) is a form of immunotherapy for allergic disorders in which the patient is vaccinated with increasingly larger doses of an allergen (substances to which they are allergic) with the aim of inducing immunologic tolerance. Allergen specific immunotherapy is the only treatment strategy which treats the underlying cause of the allergic disorder. It is a highly cost-effective treatment strategy which results in an improved quality of life and a reduction in allergic- and allergen-related asthma, as well as a reduction in days off school/work. Immunotherapy has been shown to produce long-term remission of allergic symptoms, reduce severity of associated asthma as well as reduce the chances of new sensitisations to allergens developing. This is achieved via immunotherapy modulating the immune system response to allergens.
Allergen immunotherapy can either reduce the need for medication, severity of symptoms or eliminate hypersensitivity altogether. Therapy can be administered under the tongue (sublingually) or by injections under the skin (subcutaneous). Allergen-specific immunotherapy is the only known treatment option that is known to modify the allergy disease process (with a possible chance of curing the disease), whereas other therapies merely suppress the symptoms. Subcutaneous injection immunotherapy has been shown to be highly efficacious treatment for allergic disease, but due to a rare serious side effect of anaphylaxis, its use is restricted to specialist centers. As a result there has been growing interest in the sublingual therapy which can be safely administered at home.
Allergic rhinitis is an extremely common disorder. For example in the UK 1 in 5 people have allergic rhinitis with approximately 50 percent of those with allergic rhinitis being allergic to grass pollen. Over half of people receiving symptom based treatments report that they only get partial or a poor benefit from symptomatic based treatments. For these such patients immunodesensitisation therapy can be recommended. Subcutaneous injection based immunotherapy is one effective route but is complicated by rare but serious side effects. As a result of these rare but serious side effects the sublingual route for allergen vaccination immunotherapy is gaining increasing popularity among allergy specialists due to its lack of serious side effects. A product called Grazax is currently recommended for the treatment of grass pollen allergy in the UK for patients who don't respond appropriately to symptomatic based treatment strategies.
Immunotherapy administered through cutaneous injections or sublingually has substantial empirical support. Numerous research articles and several meta-analytic studies support its clinical effectiveness. Immunotherapy can lead to a substantial decline in allergen symptomatology leading to a significant improvement in quality of life for allergy sufferers. Repeated courses of immuno-desensitisation leads to further reduction in allergy disease severity. Immunotherapy is superior to antihistamines and topical steroids in reducing severity of allergy symptoms and has been found to be a cost effective treatment strategy. Immunotherapy results in less time taken off work compared to those who rely solely on symptomatic relieving medications. In the case of grass allergy immunotherapy the pollen from the grass species used has strong cross reactivity between the various grass species thus meaning that treatment leads to desensitisation to all grass species.
Sublingual specific immunotherapy has the benefit of allowing treatment to be carried out in the home environment and has been found to be a cost effective treatment strategy for allergic disorders. Sublingual immunotherapy cost effectiveness is significantly increased due to the reduced number of medical visits compared to those receiving subcutaneous injection based immunotherapy. For example those receiving subcutaneous injections make almost seven times more visits than those receiving home based sublingual immunotherapy versus those receiving subcutaneous injections who require frequent visits to doctors to receive their regular injections. Furthermore the sublingual route appears to be equally as effective as the subcutaneous route in trials of grass allergy.
The term immunotherapy may refer not only to desensitization for allergies but also to a number of other immunomodulator techniques that aim to alter the response of the immune system in order to alleviate or cure autoimmune disease, cancer, and so forth. These include Enzyme Potentiated Desensitization (EPD) and its variant, Ultra Low Dose Enzyme Activated Immunotherapy (LDA), which have replaced "escalating dose" treatments in the U.K. but not in the U.S.
 Clinical experience and research
Immunology is a relatively young science that originated in the 19th century. Grass pollens were identified for the first time as the likely trigger of seasonal hay fever in the 1870s. Skin allergy testing became an accepted assessment technique around 1910. IgE was identified in the 1960s. The first scholarly report of immunotherapy for allergy appeared in 1911 in the medical journal, The Lancet, but research lagged behind clinical practice. Whereas clinical lore in medicine generally supports the effectiveness of immunotherapy, sufficient research evidence on the effectiveness and mechanism of immunotherapy began to accumulate in the last 15 years of the 20th century.
Some limited research of sublingual immunotherapy in children has been conducted and shown promise as a generally well tolerated treatment strategy for allergic disorders in children.
 Benefits from immunotherapy
Current pharmacotherapies (antihistamines) do not prevent allergic reaction, but instead block the action of histamine in the body, reducing allergic symptoms. Immunotherapy, in contrast, trains the immune system to tolerate allergic triggers by means of gradual exposure to increasing amounts of the offending allergen. The benefits of allergen specific immunotherapy are long lasting unlike symptomatic based treatments. Immunotherapy is most effective for pollen, dust, and animal dander allergies, and may help those with asthma.
Treatment started 10 â 14 weeks before the start of the grass pollen season results in a 34% reduction of rhinoconjunctivitis symptoms and a 54% increase in well days. Continued treatment over 2 years in the case of grass allergy shows progressive immunological changes resulting in progressive desensitisation to the allergen with up to an 73 percent reduction in symptomatology. About 3 in 4 patients with hay fever experience significant improvement with immunotherapy after one year of therapy. However, with continued therapy the number of people benefiting from specific immunotherapy appears to increase to over 4 in 5 people who benefit from specific immunotherapy by the end of the 2nd year of therapy. Sometimes symptoms are reduced rather than abolished. In that case immunotherapy may allow the patient to reduce the quantity of medication required for symptom relief.
Research in children aged from 5 years old to 16 years old shows similar effectiveness in the treatment of grass allergy as seen in adults. Like in adults allergen related asthma also decreases as well as allergic rhinitis symptoms. Recent studies in children suggest that if immunotherapy is commenced soon after allergies first develop, it may actually reduce the risk of developing allergic reactions to other allergens, and even reduce the risk of later developing asthma.
Immunotherapy is also an essential part of managing dangerous allergic reactions (anaphylaxis) to bee and wasp stings. In these cases, the protection against further dangerous allergic reactions to stinging insects is variously quoted at between 80 and 95%.
 Mechanism of therapeutic action
The immune system of allergy affected individuals, for reasons not fully understood, misinterprets a usually innocuous substance as a disease agent and begins producing a type of antibody against it, called immunoglobulin E (IgE). This is called the 'primary antibody response.' The IgE produced during this response binds to basophils in the bloodstream and to a similar type of cell called mast cells in the tissues. When the person again encounters the allergen, these basophils and mast cells that have bound to IgE release histamine, prostaglandins, and leukotrienes, which causes inflammation of the surrounding tissues, resulting in allergic symptoms.
Even the most allergic individual can tolerate minuscule amounts of an allergen without experiencing symptoms. Immunotherapy commences with the subcutaneous injection of a tiny amount of offending allergen, and gradually increases the dose until the individual's immune system is essentially 'retrained' to tolerate exposure without producing an allergic response. This process is also known as specific immunotherapy.
Immunotherapy via repeated exposure to a specific allergen via either sublingual or subcutaneous route leads to a desensitisation to the allergen and thus a reduction in allergic symptomatology and use of symptomatic based treatments. The exact mechanism is not fully understood but it is accepted that immunotherapy causes modification of the immune system. This modification leads to changes in IgE synthesis and the production of IgE blocking antibodies which thus reduces the immune systems allergic response to specific allergens. There is also an increase in Th2 to the regulatory T cells. The molecular mechanism of such immunotherapy can be partly interpreted as that there occurs induction of allergen-specific IgG to neutralize the allergen instead of induction of allergen-specific IgE. In bee or wasp venom immunotherapy, immunoglobulin subclass IgG4 has been considered to be particularly important, where IL-4 and IL-13 make the B cells to switch the produced immunoglobulin class from IgE to IgG4. It has been revealed that the mechanism of this immunotherapy consists of some more other components. They include increased production of IL-10 which acts on Th2 or mast cells to become anergic and suppresses Th2 not to release cytokines and prevent histamine from being secreted. It was indicated that osteopontin produced by CD14+ cells induced IL-12 in antigen presenting cells to activate Th1. It was recently shown that a progressive expansion of circulating regulatory T cells was made during venom immunotherapy.
For benefits to be felt from either sublingual or injection based allergen specific immunotherapy it needs to be started 2 â 4 months before the start of the allergen season in the case of seasonal allergies. The earlier it is started the better the level of allergy protection. Sublingual immunotherapy is a safe and effective alternative to injection based immunotherapy and can be administered in the home environment. Modest benefits have been demonstrated within the first season of therapy. Treatment needs to be continued for at least 3 years to achieve maximum effectiveness in immune desensitisation to the allergen. In the case of sublingual immunotherapy there is no need to do a titrated graduated updose and therapy is generally started at the usual clinical dose.
Immunotherapy via the subcutaneous route involves the use of small hypodermic syringes which are used to inject commercial allergen extracts. Injections are normally given into the loose tissue over the back of the upper arm, half way between the shoulder and elbow. Injections are given under the skin ("subcutaneous"). This is the least painful place to inject allergen, as there are few nerve endings in the skin. When given correctly, the injections should be only slightly uncomfortable. They are not normally painful and are usually well tolerated by adults and teenagers. Some doctors may advise you to take an antihistamine a few hours before each injection to reduce the likelihood of local discomfort and other side-effects.
Allergy injections are started at very low doses. The dose is gradually increased on a regular (and usually weekly) basis, until a "maintenance" dose is reached. This usually means four to six months of weekly injections to reach the maintenance dose. Once the maintenance dose is reached, the injections are administered less often (every two to four weeks), still on a regular basis. Maintenance injections are normally given once per month for a few years. Generally, the longer the treatment and the higher the dose, the greater the therapeutic benefit.
After successful completion of immunotherapy, long-term protection can be expected for a period of 3â5 years or more. Therapy can be repeated should symptoms begin to return or if the individual becomes exposed to new allergens that were not included in the previous treatment regiment. This form of treatment is covered by the vast majority of insurance companies in the United States, because allergy vaccine injections have a strong evidence base for clinical effectiveness.
In some countries, particularly in Europe, there is a strong tradition of undertaking immunotherapy using oral vaccines or sublingual drops. While there has been some interesting research in this area in recent years, the effectiveness of this form of treatment is difficult to compare with standard injected immunotherapy. Double-blind, placebo-controlled studies in Europe using high-dose sublingual immunotherapy have shown benefit. However, this form of treatment is not approved or licensed in the United States. Some practitioners in the United States, particularly ENT physicians, offer sublingual immunotherapy as another immunotherapy option.
 Side effects and adverse reactions
A relatively large but normative localized reaction to an allergy injection on the upper arm of a patient. This reaction would not cause concern, but larger reactions may require a readjustment of the treatment regimen.
Itchiness, swelling, and redness at the site of injection are expected. Systemic reactions such as hives or anaphylaxis occur rarely and need to be treated immediately. If such reactions occur, the allergy specialist will adjust the dosage to a safe level. Patients are advised or required to wait in the clinic for 20â30 minutes so that they can be treated immediately in the case that they develop a severe systemic reaction. The risk of a systemic reaction is reduced if the patient avoids exercising or overheating for a few hours before and after the procedure. Some heart and blood pressure medications such as beta-blockers are contraindicated as well.
The physician should be consulted if the patient notices a worsening of allergy symptoms or if he or she is suffering from a cold or has been undergoing a different kind of vaccination procedure. Immunotherapy does not increase the risk of contracting a cold.
The side effects of sublingual desensitisation therapy are generally mild and limited to local reactions. Common side effects include oral pruritus, edema mouth, ear pruritus, throat irritation, sneezing, mild itching and swelling of the mouth. Side effects which are less common or rare include headache, oral paraesthesia, eye pruritus, conjunctivitis, cough, asthma, pharyngitis, rhinorrhoea, nasal congestion, rhinitis, throat tightness, pruritus and fatigue. In most cases these side effects diminished minutes or hours after immunotherapy and disappeared 1 â 7 days after commencement of therapy. As a precautionary measure against rare but serious side effects eg asthma attacks it is recommended that the first sublingual tablet containing the specific allergen for immunotherapy is administrated whilst under the observation of a medical doctor and observed for 30 minutes for any signs of serious side effects.
Sublingual immunotherapy is contraindicated in patients who have systemic diseases of the immune system, inflammatory conditions of the oral cavity with associated severe symptoms eg oral lichen planus with ulcers or severe oral mycosis or individuals with severe and uncontrolled asthma. Immunotherapy tablets are also contraindicated in individuals who are allergic to any of the addition constituents of the tablet.
 See also
- ^ Nasser S, Vestenbaek U, Beriot-Mathiot A, Poulsen PB (December 2008). "Cost-effectiveness of specific immunotherapy with Grazax in allergic rhinitis co-existing with asthma". Allergy 63 (12): 1624â9. doi:10.1111/j.1398-9995.2008.01743.x. PMID 19032235. http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0105-4538&date=2008&volume=63&issue=12&spage=1624.
- ^ a b c d e f g h i CalderΓ³n M, Brandt T (December 2008). "Treatment of grass pollen allergy: focus on a standardized grass allergen extract - Grazax". Ther Clin Risk Manag 4 (6): 1255â60. PMID 19337432.
- ^ Durham SR, Yang WH, Pedersen MR, Johansen N, Rak S (April 2006). "Sublingual immunotherapy with once-daily grass allergen tablets: a randomized controlled trial in seasonal allergic rhinoconjunctivitis". J. Allergy Clin. Immunol. 117 (4): 802â9. doi:10.1016/j.jaci.2005.12.1358. PMID 16630937. http://linkinghub.elsevier.com/retrieve/pii/S0091-6749(06)00291-0.
- ^ Kay AB (December 2007). "An extract of Timothy-grass pollen used as sublingual immunotherapy for summer hay fever". Drugs Today 43 (12): 841â8. doi:10.1358/dot.2007.43.12.1162079. PMID 18174969. http://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summaryn_pr?p_JournalId=4&p_RefId=1162079.
- ^ Bmj, Group (February 2008). "Grazax for hay fever?". Drug Ther Bull 46 (2): 9â10. doi:10.1136/dtb.2008.01.0001. PMID 18256175. http://dtb.bmj.com/cgi/pmidlookup?view=long&pmid=18256175.
- ^ Rak S, Yang WH, Pedersen MR, Durham SR (March 2007). "Once-daily sublingual allergen-specific immunotherapy improves quality of life in patients with grass pollen-induced allergic rhinoconjunctivitis: a double-blind, randomised study". Qual Life Res 16 (2): 191â201. doi:10.1007/s11136-006-9110-3. PMID 17033900.
- ^ Bachert C, Vestenbaek U, Christensen J, Griffiths UK, Poulsen PB (May 2007). "Cost-effectiveness of grass allergen tablet (GRAZAX) for the prevention of seasonal grass pollen induced rhinoconjunctivitis - a Northern European perspective". Clin. Exp. Allergy 37 (5): 772â9. doi:10.1111/j.1365-2222.2007.02706.x. PMID 17456225. http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0954-7894&date=2007&volume=37&issue=5&spage=772.
- ^ Canonica GW, Poulsen PB, Vestenbaek U (September 2007). "Cost-effectiveness of GRAZAX for prevention of grass pollen induced rhinoconjunctivitis in Southern Europe". Respir Med 101 (9): 1885â94. doi:10.1016/j.rmed.2007.05.003. PMID 17611095. http://linkinghub.elsevier.com/retrieve/pii/S0954-6111(07)00190-4.
- ^ Poulsen PB, Pedersen KM, Christensen J, Vestenbaek U (January 2008). "[Economic evaluation of a tablet-based vaccination against hay fever in Denmark]" (in Danish). Ugeskr. Laeg. 170 (3): 138â42. PMID 18208729.
- ^ World Allergy Organization | Allergic Diseases Resource Center
- ^ IbaΓ±ez MD, Kaiser F, Knecht R, et al (September 2007). "Safety of specific sublingual immunotherapy with SQ standardized grass allergen tablets in children". Pediatr Allergy Immunol 18 (6): 516â22. doi:10.1111/j.1399-3038.2007.00556.x. PMID 17680910. http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0905-6157&date=2007&volume=18&issue=6&spage=516.
- ^ Durham SR, Riis B (August 2007). "Grass allergen tablet immunotherapy relieves individual seasonal eye and nasal symptoms, including nasal blockage". Allergy 62 (8): 954â7. doi:10.1111/j.1398-9995.2007.01402.x. PMID 17620075. http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0105-4538&date=2007&volume=62&issue=8&spage=954.
- ^ Introduction: Allergic Reactions: Merck Manual Home Edition
- ^ Dahl R, Stender A, Rak S (February 2006). "Specific immunotherapy with SQ standardized grass allergen tablets in asthmatics with rhinoconjunctivitis". Allergy 61 (2): 185â90. doi:10.1111/j.1398-9995.2005.00949.x. PMID 16409194. http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0105-4538&date=2006&volume=61&issue=2&spage=185.
- ^ Dahl R, Kapp A, Colombo G, et al (February 2008). "Sublingual grass allergen tablet immunotherapy provides sustained clinical benefit with progressive immunologic changes over 2 years". J. Allergy Clin. Immunol. 121 (2): 512â518.e2. doi:10.1016/j.jaci.2007.10.039. PMID 18155284. http://linkinghub.elsevier.com/retrieve/pii/S0091-6749(07)02166-5.
- ^ Bufe A, Eberle P, Franke-Beckmann E, et al (January 2009). "Safety and efficacy in children of an SQ-standardized grass allergen tablet for sublingual immunotherapy". J. Allergy Clin. Immunol. 123 (1): 167â173.e7. doi:10.1016/j.jaci.2008.10.044. PMID 19130937. http://linkinghub.elsevier.com/retrieve/pii/S0091-6749(08)01921-0.
- ^ a b Hirata H, Arima M, Yukawa T (2000). "Effect of rush immunotherapy (RIT) on cytokine production in hymenoptera allergy". Dokkyo J Med Sci 27 (1): 27â40.
- ^ Del Prete G, Maggi E, Parronchi P, et al. (June 1988). "IL-4 is an essential factor for the IgE synthesis induced in vitro by human T cell clones and their supernatants". J. Immunol. 140 (12): 4193â8. PMID 2967330. http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=2967330.
- ^ Punnonen J, Aversa G, Cocks BG, et al. (April 1993). "Interleukin 13 induces interleukin 4-independent IgG4 and IgE synthesis and CD23 expression by human B cells". Proc. Natl. Acad. Sci. U.S.A. 90 (8): 3730â4. doi:10.1073/pnas.90.8.3730. PMID 8097323.
- ^ Akdis CA, Blesken T, Akdis M, WΓΌthrich B, Blaser K (July 1998). "Role of interleukin 10 in specific immunotherapy". J. Clin. Invest. 102 (1): 98â106. doi:10.1172/JCI2250. PMID 9649562.
- ^ Konno S, Golden DB, Schroeder J, Hamilton RG, Lichtenstein LM, Huang SK (May 2005). "Increased expression of osteopontin is associated with long-term bee venom immunotherapy". J. Allergy Clin. Immunol. 115 (5): 1063â7. doi:10.1016/j.jaci.2005.01.055. PMID 15867867. http://linkinghub.elsevier.com/retrieve/pii/S0091674905002265.
- ^ Pereira-Santos MC, Baptista AP, Melo A, et al. (February 2008). "Expansion of circulating Foxp3+D25bright CD4+ T cells during specific venom immunotherapy". Clin. Exp. Allergy 38 (2): 291â7. doi:10.1111/j.1365-2222.2007.02887.x (inactive 2009-12-19). PMID 18070166. http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0954-7894&date=2008&volume=38&issue=2&spage=291.
- ^ Calderon MA, Birk AO, Andersen JS, Durham SR (August 2007). "Prolonged preseasonal treatment phase with Grazax sublingual immunotherapy increases clinical efficacy". Allergy 62 (8): 958â61. doi:10.1111/j.1398-9995.2007.01416.x. PMID 17620076. http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0105-4538&date=2007&volume=62&issue=8&spage=958.
- ^ Allison C, Fraser J (November 2007). "Grazax: an oral vaccine for the treatment of grass pollen allergy (hay fever)". Issues Emerg Health Technol (107): 1â4. PMID 18041171.
- ^ Svendsen UG (January 2008). "[Grazaxâtreatment for grass pollen hay fever]" (in Danish). Ugeskr. Laeg. 170 (3): 135â7. PMID 18208728.
- ^ Smith H, White P, Annila I, Poole J, Andre C, Frew A (October 2004). "Randomized controlled trial of high-dose sublingual immunotherapy to treat seasonal allergic rhinitis". J. Allergy Clin. Immunol. 114 (4): 831â7. doi:10.1016/j.jaci.2004.06.058. PMID 15480323. http://linkinghub.elsevier.com/retrieve/pii/S0091674904022316.
- ^ Dahl R, Kapp A, Colombo G, et al (August 2006). "Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis". J. Allergy Clin. Immunol. 118 (2): 434â40. doi:10.1016/j.jaci.2006.05.003. PMID 16890769. http://linkinghub.elsevier.com/retrieve/pii/S0091-6749(06)01135-3.
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