Allergen immunotherapy

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Allergen immunotherapy
Alutard SQ.jpg
An Alutard SQ injection kit
Other namesDesensitization, hypo-sensitization

Allergen immunotherapy, also known as desensitization or hypo-sensitization, is a medical treatment for environmental allergies, such as insect bites, and asthma. [1] [2] Immunotherapy involves exposing people to larger and larger amounts of allergens in an attempt to change the immune system's response. [1]

Contents

Meta-analyses have found that injections of allergens under the skin are effective in the treatment of allergic rhinitis in children [3] [4] and in asthma. [2] The benefits may last for years after treatment is stopped. [5] It is generally safe and effective for allergic rhinitis, allergic conjunctivitis, allergic forms of asthma, and stinging insects. [6] The evidence also supports the use of sublingual immunotherapy against rhinitis and asthma, but it is less strong. [5] In this form the allergen is given under the tongue and people often prefer it to injections. [5] Immunotherapy is not recommended as a stand-alone treatment for asthma. [5]

Side effects during sublingual immunotherapy treatment are usually local and mild and can often be eliminated by adjusting the dosage. [7] Anaphylaxis during sublingual immunotherapy treatment has occurred on rare occasions. [7]

Potential side effects related to subcutaneous immunotherapy treatment for asthma and allergic rhinoconjunctivitis include mild or moderate skin or respiratory reactions. [8] Severe side effects such as anaphylaxis during subcutaneous immunotherapy treatment are relatively uncommon. [8]

Discovered by Leonard Noon and John Freeman in 1911, allergen immunotherapy is the only medicine known to tackle not only the symptoms but also the causes of respiratory allergies. [9] A detailed diagnosis is necessary to identify the allergens involved. [10]

Types

Subcutaneous

Subcutaneous immunotherapy (SCIT), also known as allergy shots, is the historical route of administration and consists of injections of allergen extract, which must be performed by a medical professional. Subcutaneous immunotherapy protocols generally involve weekly injections during a build-up phase, followed by a monthly maintenance phase that consists of injections for a period of 3–5 years. [11] The build-up phase involves the patient being administered injections which contain increasing amounts of allergens about one to two times per week. The length of the build-up phase is dependent upon how often injections are administered, but normally ranges from three to six months. After the effective dose is reached, the maintenance phase is implemented, which varies depending upon an individual's response to the build-up phase. [12]

When accounting for a person's age, type of allergen, and severity of allergy, there is a high probability that subcutaneous allergen immunotherapy may provide greater clinical and immunological responses than sublingual allergen immunotherapy. [13] Compared to sublingual allergen immunotherapy, there are no significant differences observed in quality of life. [13]

It is possible, but rare (1/2.5 million), that people undergoing subcutaneous allergen immunotherapy may experience a fatal anaphylactic event. [14] Subcutaneous allergen immunotherapy adverse events vary significantly depending on different allergenic extracts and the application of different allergen immunotherapy schedules. [14]

Allergen immunotherapy schedules include the "cluster" approach, which involves administering several doses sequentially in a single day; a "conventional" approach, which involves incrementally increasing the dose over approximately 15 weeks; and the "rush" approach, which involves administering incremental doses at intervals of 15–60 minutes over 1–3 days. [14]

It is challenging to perform an adequate risk assessment on the use of subcutaneous allergen immunotherapy compared to other forms of allergen immunotherapy administration due to the variability of immunotherapy schedules and further research is required. [14]

Sublingual

Sublingual immunotherapy involves putting drops or a tablet of allergen extracts under the tongue, which are then absorbed through the lining of the mouth. Sublingual immunotherapy has been demonstrated to be effective against rhinoconjunctivitis and asthma symptoms. [15] This effectiveness, however, varies depending on the type of allergen. [15] The strongest evidence for the efficacy of sublingual immunotherapy comes from studies that used grass allergens or mite allergens to alleviate allergic rhinitis symptoms; the evidence shows modest improvement. [16]

Sublingual immunotherapy is used to treat allergic rhinitis, often from seasonal allergies, and is typically given in several doses over a 12-week period. [17] It works best when given 12 weeks before the start of the pollen season. [17] The first dose is given by a physician to monitor for any rare reactions or anaphylaxis. [17] Subsequent doses can be taken at home [17] which makes this a convenient alternative to subcutaneous immunotherapy.

While a number of side effects have been associated with sublingual immunotherapy, serious adverse effects are very rare (about 1.4/100,000 doses), and there has not been a reported fatality. [15] There have been a small number of reports of anaphylaxis. [15] The majority of side effects are 'local' and usually resolve within a few days. [15] They include swelling of the mouth, tongue or lip, throat irritation, nausea, abdominal pain, vomiting, diarrhea, heartburn, and uvular edema. [15] It is not yet clear if there are any risk factors that might increase a person's susceptibility to these adverse effects. [15] Sublingual immunotherapy appears to be better tolerated than subcutaneous immunotherapy and causes fewer side effects. [15] The safety of sublingual immunotherapy has not been studied extensively in people with chronic immunodeficiency or autoimmune disorders. [15]

Oral

Oral immunotherapy (OIT) involves feeding an allergic individual increasing amounts of a food allergen in order to raise the threshold which triggers a reaction. [18] Long-term, many study participants still experienced mild allergic reactions or needed to regularly consume the allergen to maintain desensitivity. [19] Additionally, oral immunotherapy is known to have an increased risk in the probability of needing epinephrine in patients who take it. [20] Currently, the U.S. Food and Drug Administration has not approved any oral immunotherapy agents for asthma. [21] In January 2020, the FDA approved Palforzia for mitigating "allergic reactions, including anaphylaxis, that may occur with accidental exposure to peanuts." [22] [23] It is the first drug approved for peanut allergies. It will not allow allergic people able to eat normal amounts of peanuts, but helps prevent allergies due to accidental eating. [24]

Transdermal

Transdermal immunotherapy (TDIT) involves skin-induced suppression via epicutaneous (EC) application of an antigen in order to raise the threshold which triggers a reaction. [25]

Mechanism of action

In desensitization immunotherapy the aim is to induce or restore tolerance to the allergen by reducing its tendency to induce IgE production. People are desensitized through the administration of escalating doses of allergen that gradually decreases the IgE-dominated response. The objective of immunotherapy is to direct the immune response away from humoral immunity and toward cellular immunity, thereby encouraging the body to produce fewer IgE antibodies and more CD4+ T regulatory cells that secrete IL-10 and TGF-β, which skews the response away from IgE production. [26]

Oral immunotherapy also creates an increase in allergen-specific IgG4 antibodies and a decrease in allergen-specific IgE antibodies, as well as diminished mast cells and basophils, two cell types that are large contributors to allergic reaction. [27] [28]

Protocol

Reactivity is tested using oral food challenges or with skin prick tests. Phases 1 & 2 of sublingual immunotherapy are conducted in a supervised clinical setting. However, phase 3 can be done at home. [27]

History

In the late 19th century and early 20th century, allergic conditions were increasingly attracting both medical attention (as an emerging public health problem) and scientific interest (aided by progress in biochemical techniques and the development of molecular and pathogenic theories). However, the many and varied treatment approaches were very unscientific.[ citation needed ]

The British physicians Noon and Freeman were the first researchers to test pollen allergen immunotherapy in humans. Noon and Freeman, researchers at the Department of Therapeutic Inoculation at St. Mary's Hospital in London, published their findings in The Lancet in 1911. [29] [30] [ non-primary source needed ][ failed verification ] Building on the observations of his predecessors Bostock, Blackley and Dunbar, Noon noted that people with hay fever "sometimes become cured" and that this was possibly because they "have had the good fortune to develop an active immunity against the toxin." He hypothesized that by injecting people with hay fever with small amounts of a pollen "toxin", a state of immunity could be achieved. [31]

Allergen immunotherapy was part of mainstream medical practice for hay fever treatment in the 1930s.[ citation needed ]

Society and culture

Sublingual immunotherapy drops are currently commercialized and used in most European and South American countries, and in Australia and Asian countries. In most European countries, national regulations allow marketing of allergen products as "named patient preparations" (NPPs). In the United States, drop formulations have not yet received FDA approval, though off-label prescription is becoming common. [32] In 2014, the FDA approved a once-daily sublingual tablet containing allergen extracts for the treatment of "hay fever" (allergic rhinitis with or without conjunctivitis). [33]

Recognition by international agencies

The use of subcutaneous immunotherapy for treatment of environmental-based allergies and asthma is well supported by the majority of national and international allergy groups such as the World Allergy Organization, Canadian Society of Allergy and Immunology, European Academy of Allergy and Clinical Immunology, and the American Academy of Allergy, Asthma and Immunology. [34] The use of sublingual immunotherapy is supported by few allergy agencies in order to allow for more investigation to occur on its practical use. [34] Oral immunotherapy is generally not recommended, however the EAACI recommends that this treatment only be administered at specialized centres with expert professionals. [34]

Subcutaneous immunotherapy is both approved and regulated by the American Food and Drug Administration (FDA) and the European Medicinal Agency (EMEA). [35] The FDA currently allows individual allergists to create the formula for each dosage, whereas the EMEA requires treatment extracts to be prepared at manufacturing sites. [35] The FDA has approved sublingual therapy through the use of tablets, but has not approved specific formulation. [35] The EMEA has also approved sublingual therapy through both tablets and solution, and this administration now accounts for 45% of immunotherapy treatments. [35]

The FDA advisory board has supported the use of AR101, an oral immunotherapy, for patients with peanut allergies in 2019. [20]

Science communication

Allergen immunotherapy is viewed as a beneficial way to curb allergies in the perspective of the media. It is seen where it can be covered by insurance and offer a more permanent solution than antihistamines or nasal steroids that treat symptoms, not the body's reaction. [36] Communication about allergen immunotherapy is not described very often in the news media; it is usually only communicated by the science community. The scientific community describes allergen immunotherapy as a scientific solution that helps not only patients with allergies but also positively impacts the quality of life of them and others around them. As temperatures increase due to changing climates, pollen levels also increase. [37] Allergies are becoming a more common problem among the public, which is why the science community advocates for allergen immunotherapy. Subcutaneous allergen immunotherapy, according to the scientific community, is an effective solution to allergies due to numerous positive studies. [38]

Research

Oral immunotherapy

As of 2015, oral immunotherapy's balance of risk to benefit for food allergies was not well studied. [1] As of 2011, OIT was under investigation as a treatment for a variety of common food allergies including peanuts, milk, and eggs. Studies involving OIT have shown desensitization towards the allergen. However, there are still questions about longevity of tolerance after the study has ended. [39] [27] However, almost every study has excluded people with severe allergen-induced anaphylaxis. [28]

One approach being studied is in altering the protein structure of the allergen to decrease immune response but still induce tolerance. Extensive heating of some foods can change the conformation of epitopes recognized by IgE antibodies. In fact, studies show that regular consumption of heated food allergens can speed up allergy resolution. In one study, subjects allergic to milk were 16x more likely to develop complete milk tolerance compared to complete milk avoidance. Another approach regarding changes in protein is to change specific amino acids in the protein to decrease recognition of the allergen by allergen-specific antibodies. [28]

Another approach to improving oral immunotherapy is to change the immune environment to prevent TH2 cells from responding to the allergens during treatment. For example, drugs that inhibit IgE-mediated signaling pathways can be used in addition to OIT to reduce immune response. In 1 trial, the monoclonal antibody omalizumab was combined with high-dose milk oral immunotherapy and saw positive results. Several other trials are also currently being done combining omalizumab with OIT for a variety of food allergens. FAHF-2, a Chinese herbal mixture, has shown positive effects on the immune system and has been shown to protect mice from peanut-induced anaphylaxis. FAHF-2 was also well tolerated in a phase I study. While it is possible that omalizumab, FAHF-2 or other immunomodulatory agents alone might be able to treat dangerous allergies, combining these with OIT may be more effective and synergistic, warranting further investigation. [28]

In addition, various adjuvants (nanoparticles) is a field of development that can be used for OIT. With the potential to modulate antigen release, it may one day be possible to take a pill containing nanoparticles that will modulate dosing, requiring fewer office visits. [28]

Studies have also been done to determine the efficacy of OIT for multiple allergens simultaneously. One study concluded that multi-OIT would be possible and relatively, though larger studies would be necessary. [40]

Related Research Articles

<span class="mw-page-title-main">Allergy</span> Immune system response to a substance that most people tolerate well

Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermatitis, allergic asthma, and anaphylaxis. Symptoms may include red eyes, an itchy rash, sneezing, coughing, a runny nose, shortness of breath, or swelling. Note that food intolerances and food poisoning are separate conditions.

An allergen is a type of antigen that produces an abnormally vigorous immune response in which the immune system fights off a perceived threat that would otherwise be harmless to the body. Such reactions are called allergies.

<span class="mw-page-title-main">Anaphylaxis</span> Life-threatening allergic reaction

Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the following: an itchy rash, throat closing due to swelling that can obstruct or stop breathing; severe tongue swelling that can also interfere with or stop breathing; shortness of breath, vomiting, lightheadedness, loss of consciousness, low blood pressure, and medical shock. These symptoms typically start in minutes to hours and then increase very rapidly to life-threatening levels. Urgent medical treatment is required to prevent serious harm and death, even if the patient has used an epipen or has taken other medications in response, and even if symptoms appear to be improving.

<span class="mw-page-title-main">Allergic rhinitis</span> Nasal inflammation due to allergens in the air

Allergic rhinitis, of which the seasonal type is called hay fever, is a type of inflammation in the nose that occurs when the immune system overreacts to allergens in the air. Signs and symptoms include a runny or stuffy nose, sneezing, red, itchy, and watery eyes, and swelling around the eyes. The fluid from the nose is usually clear. Symptom onset is often within minutes following allergen exposure, and can affect sleep and the ability to work or study. Some people may develop symptoms only during specific times of the year, often as a result of pollen exposure. Many people with allergic rhinitis also have asthma, allergic conjunctivitis, or atopic dermatitis.

<span class="mw-page-title-main">Immunoglobulin E</span> Immunoglobulin E (IgE) Antibody

Immunoglobulin E (IgE) is a type of antibody that has been found only in mammals. IgE is synthesised by plasma cells. Monomers of IgE consist of two heavy chains and two light chains, with the ε chain containing four Ig-like constant domains (Cε1–Cε4). IgE is thought to be an important part of the immune response against infection by certain parasitic worms, including Schistosoma mansoni, Trichinella spiralis, and Fasciola hepatica. IgE is also utilized during immune defense against certain protozoan parasites such as Plasmodium falciparum. IgE may have evolved as a defense to protect against venoms.

<span class="mw-page-title-main">Food allergy</span> Hypersensitivity reaction to a food

A food allergy is an abnormal immune response to food. The symptoms of the allergic reaction may range from mild to severe. They may include itchiness, swelling of the tongue, vomiting, diarrhea, hives, trouble breathing, or low blood pressure. This typically occurs within minutes to several hours of exposure. When the symptoms are severe, it is known as anaphylaxis. A food intolerance and food poisoning are separate conditions, not due to an immune response.

Omalizumab, sold under the brand name Xolair, is a medication to treat asthma, nasal polyps, and urticaria (hives).

<span class="mw-page-title-main">Allergic conjunctivitis</span> Medical condition

Allergic conjunctivitis (AC) is inflammation of the conjunctiva due to allergy. Although allergens differ among patients, the most common cause is hay fever. Symptoms consist of redness, edema (swelling) of the conjunctiva, itching, and increased lacrimation. If this is combined with rhinitis, the condition is termed allergic rhinoconjunctivitis (ARC).

<span class="mw-page-title-main">Atopy</span> Predisposition towards allergy

Atopy is the tendency to produce an exaggerated immunoglobulin E (IgE) immune response to otherwise harmless substances in the environment. Allergic diseases are clinical manifestations of such inappropriate, atopic responses.

<span class="mw-page-title-main">Peanut allergy</span> Type of food allergy caused by peanuts

Peanut allergy is a type of food allergy to peanuts. It is different from tree nut allergies, because peanuts are legumes and not true nuts. Physical symptoms of allergic reaction can include itchiness, hives, swelling, eczema, sneezing, asthma attack, abdominal pain, drop in blood pressure, diarrhea, and cardiac arrest. Anaphylaxis may occur. Those with a history of asthma are more likely to be severely affected.

<span class="mw-page-title-main">Soy allergy</span> Type of food allergy caused by soy

Soy allergy is a type of food allergy. It is a hypersensitivity to ingesting compounds in soy, causing an overreaction of the immune system, typically with physical symptoms, such as gastrointestinal discomfort, respiratory distress, or a skin reaction. Soy is among the eight most common foods inducing allergic reactions in children and adults. It has a prevalence of about 0.3% in the general population.

<span class="mw-page-title-main">Milk allergy</span> Type of food allergy caused by milk

Milk allergy is an adverse immune reaction to one or more proteins in cow's milk. Symptoms may take hours to days to manifest, with symptoms including atopic dermatitis, inflammation of the esophagus, enteropathy involving the small intestine and proctocolitis involving the rectum and colon. However, rapid anaphylaxis is possible, a potentially life-threatening condition that requires treatment with epinephrine, among other measures.

<span class="mw-page-title-main">Egg allergy</span> Type of food allergy caused by eggs

Egg allergy is an immune hypersensitivity to proteins found in chicken eggs, and possibly goose, duck, or turkey eggs. Symptoms can be either rapid or gradual in onset. The latter can take hours to days to appear. The former may include anaphylaxis, a potentially life-threatening condition which requires treatment with epinephrine. Other presentations may include atopic dermatitis or inflammation of the esophagus.

<span class="mw-page-title-main">Tree nut allergy</span> Medical condition

A tree nut allergy is a hypersensitivity to dietary substances from tree nuts and edible tree seeds causing an overreaction of the immune system which may lead to severe physical symptoms. Tree nuts include almonds, Brazil nuts, cashews, chestnuts, filberts/hazelnuts, macadamia nuts, pecans, pistachios, shea nuts and walnuts.

Enzyme potentiated desensitization (EPD), is a treatment for allergies developed in the 1960s by Dr. Leonard M. McEwen in the United Kingdom. EPD uses much lower doses of antigens than conventional desensitization treatment paired with the enzyme β-glucuronidase. EPD is approved in the United Kingdom for the treatment of hay fever, food allergy and intolerance and environmental allergies.

Peanut Allergen Powder, sold under the brand name Palforzia, is an oral medication for the treatment of allergic reactions, including anaphylaxis, in children typically aged between four and 17 years of age who have confirmed cases of peanut allergy. It is taken by mouth.

<span class="mw-page-title-main">Fish allergy</span> Type of food allergy caused by fish

Fish allergy is an immune hypersensitivity to proteins found in fish. Symptoms can be either rapid or gradual in onset. The latter can take hours to days to appear. The former may include anaphylaxis, a potentially life-threatening condition which requires treatment with epinephrine. Other presentations may include atopic dermatitis or inflammation of the esophagus. Fish is one of the eight common food allergens which are responsible for 90% of allergic reactions to foods: cow's milk, eggs, wheat, shellfish, peanuts, tree nuts, fish, and soy beans.

<span class="mw-page-title-main">Dust mite allergy</span> Medical condition

Dust mite allergy, also known as house dust allergy, is a sensitization and allergic reaction to the droppings of house dust mites. The allergy is common and can trigger allergic reactions such as asthma, eczema or itching. The mite's gut contains potent digestive enzymes that persist in their feces and are major inducers of allergic reactions such as wheezing. The mite's exoskeleton can also contribute to allergic reactions. Unlike scabies mites or skin follicle mites, house dust mites do not burrow under the skin and are not parasitic.

<span class="mw-page-title-main">Shellfish allergy</span> Type of food allergy caused by shellfish

Shellfish allergy is among the most common food allergies. "Shellfish" is a colloquial and fisheries term for aquatic invertebrates used as food, including various species of molluscs such as clams, mussels, oysters and scallops, crustaceans such as shrimp, lobsters and crabs, and cephalopods such as squid and octopus. Shellfish allergy is an immune hypersensitivity to proteins found in shellfish. Symptoms can be either rapid or gradual in onset. The latter can take hours to days to appear. The former may include anaphylaxis, a potentially life-threatening condition which requires treatment with epinephrine. Other presentations may include atopic dermatitis or inflammation of the esophagus. Shellfish is one of the eight common food allergens, responsible for 90% of allergic reactions to foods: cow's milk, eggs, wheat, shellfish, peanuts, tree nuts, fish, and soy beans.

<span class="mw-page-title-main">Sesame allergy</span> Food allergy caused by sesame seeds

A food allergy to sesame seeds has prevalence estimates in the range of 0.1–0.2% of the general population, and are higher in the Middle East and other countries where sesame seeds are used in traditional foods. Reporting of sesame seed allergy has increased in the 21st century, either due to a true increase from exposure to more sesame foods or due to an increase in awareness. Increasing sesame allergy rates have induced more countries to regulate food labels to identify sesame ingredients in products and the potential for allergy. In the United States, sesame became the ninth food allergen with mandatory labeling, effective 1 January 2023.

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