Immunotherapy for Allergies

Allergen immunotherapy can provide significant improvements in allergic symptoms and reduce the need for additional pharmacotherapy. Allergen immunotherapy has been clinically demonstrated to provide long-term clinical benefits, including symptomatic disease remission and a reduction in allergic disease progression from rhinitis to asthma.[1]

The first report describing immunotherapy was published in 1911, when Noon described that the subcutaneous injection of a pollen extract suppressed allergen-induced symptoms. Since then, allergen immunotherapy has been used in medical practice to successfully treat hypersensitivity to many allergens, including dust mites, grass, ragweed and tree pollen, insect venom, and animal dander. Allergen immunotherapy is appropriate for patients suffering from immunoglobulin E (IgE)–mediated allergic diseases such as seasonal allergic rhinitis, perennial rhinitis, allergic asthma, and insect venomanaphylaxis.

Aside from allergen immunotherapy, the other available treatment options for allergic diseases include aeroallergen avoidance and pharmacotherapy. In addition, surgery may be offered as an adjunct in appropriate patients (eg, septoplasty for nasal septal deviation, sinus surgery for chronic sinusitis, turbinate reduction for turbinate hypertrophy, nasal polypectomy for nasal polyps).

Effective treatment reduces symptoms and medication utilization while improving quality of life. Allergen immunotherapy has demonstrated long-term effectiveness in symptom reduction more than 3 years following treatment cessation and has prevented the development of new sensitizations in children.

Allergic pathophysiology and method of action

Within seconds to minutes of allergen exposure, mast cells initiate granule exocytosis, releasing preformed histamine, serine proteases, and proteoglycans. These series of cellular events give rise to immediate allergic symptoms that peak within 15-30 minutes and affect the skin, eyes, and both upper and lower respiratory systems. Mast cells also synthesize prostaglandins and leukotrienes and release additional proinflammatory mediators and cytokines, which increase vascular permeability and promote recruitment of other effector cells.

A second, or late phase, of allergic inflammation can occur approximately 6-12 hours after allergen exposure. This late allergic response is the result of activated CD4+ T cells, eosinophils, neutrophils, and basophils leaving the bloodstream and infiltrating the local tissue upon allergen exposure. Each of these cell types contains important mediators in the allergic response: Basophils have histamine-containing granules; eosinophils contain major basic protein and leukotrienes, particularly leukotriene C4; and neutrophils produce lipids, cytokines, and proteases that directly damage tissues, including mucosal membranes, and further augment mast cell and eosinophil activity.[2, 3, 4, 5, 6, 7, 8]

Allergen immunotherapy suppresses the allergen-induced late response and diminishes the immediate phase via prevention of allergen-driven Th2 responses, including reductions in levels of interleukin (IL)–4, IL-13, IL-5, and IL-9. Perhaps more importantly, the decrease in Th2 response is complemented by a change in the immune response to one favoring the “protective” Th1 pathways. Allergen immunotherapy induces IL-10 and transforming growth factor (TGF)-β–secreting T regulatory cells, which appear to suppress Th2 responses. Additionally, IL-10 contributes to the switching of immunoglobulin isotypes to IgG4, and TGFβ mediates switching to IgA.

The down-regulation of the allergic response in a patient undergoing allergen immunotherapy is attributed to increases in IgG1, IgG4, and IgA, and also a decrease in IgE. This alteration is affiliated with significant reductions in the numbers of infiltrating T cells, basophils, eosinophils, and neutrophils. IgG4 antibodies also block allergen-induced IgE-dependent histamine released by basophils. Allergen immunotherapy results in a long-term reduction in serum allergen-specific IgE levels. Significant reductions in the early-phase response have also been demonstrated.[9, 10, 11, 8, 12]

Sublingual immunotherapy

Sublingual immunotherapy experienced renewed interest in England after a review of safety and protocols of subcutaneous immunotherapy identified a 0.5%-5.6% rate of systemic reactions and fatalities, most commonly due to "preventable errors." These findings reduced the use of subcutaneous immunotherapy in Britain and encouraged research into allergy treatment with sublingual immunotherapy. Most of the data address monotherapy, and research has yet to delineate ideal dosing concentrations, dosing schedules, dosing duration, and duration of patient response.

In sublingual immunotherapy, the theory is that the antigen comes into contact with Langerhans-like dendritic cells residing in the oral mucosa on the floor of the mouth under the tongue. These cells capture the antigen and migrate to local lymph nodes, resulting in the production of blocking antibodies and induction of T-regulator cells, which then suppress Th-1 and Th-2 cellular response via IL-10 and TGFβ mechanisms, both of which are described in detail above.[13, 14]

Sublingual immunotherapy has been demonstrated to decrease allergen-specific IgE, bronchial reactivity, and nasal and conjunctival eosinophils and neutrophils and to increase IgG4, IL-10, TGFβ, and interferon (INF)–gamma. Significant long-lasting symptom control of allergic rhinitis, rhinoconjunctivitis, and asthma has been demonstrated in multiple studies. This method is very convenient for patients, decreases blood and latex exposure, and is believed to be quite safe , although several cases of anaphylaxis have been reported in the literature.[15, 16, 17, 18, 19, 20, 21]

Allergen immunotherapy is appropriate for patients with IgE-mediated allergic diseases such as seasonal allergic rhinitis, perennial rhinitis, allergic asthma, and insect venomanaphylaxis whose symptoms are not well controlled with avoidance measures and pharmacotherapy and in whom an IgE-mediated reaction to antigen has been documented. Some recent reports have suggested that immunotherapy may also aid in atopic dermatitis.[22, 23, 24, 25, 26, 27, 28]

Sublingual immunotherapy is contraindicated in severe asthma. In addition, there are no data available for simultaneous treatment of multiple sensitivity. It is recommended that subcutaneous immunotherapy not be given to patients with uncontrolled asthma.[29]

Best Practices

The treating physician should be familiar with allergy testing and immunotherapy, along with its risks. The physician must be equipped to expeditiously address any allergic emergency.

History

A detailed allergy history is very important to obtain when embarking on a treatment regimen in a patient who presents with allergic symptoms. The allergy history may be complex and may require several patient encounters to allow for completeness.

Examples of questions to ask for delineation of symptoms include the following:

• Symptomatic involvement of eyes, ears, nose, sinuses, lungs, or skin

• Presenting symptoms (date of onset, fluctuation, timing/seasonality, severity, aggravating and relieving factors)

• Potentially etiologic exposures

• Chronic versus acute

• Indoor versus outdoor

• Past treatment attempts (over-the-counter and prescription medications)

• Past allergy testing

• Past immunotherapy

• Any changes in lifestyle (work, leisure, diet)

• Presence of asthma and the level of disease control

A list of additional medications (eg, beta-blockers, antidepressants) should be obtained, as well as any allergies to medications or adverse reactions to aspirin.

While adverse systemic reactions are uncommon, immunotherapy should be administered by only trained personnel, and resuscitative medications and equipment should be immediately available.

Adequate equipment and medications should be immediately available in case of anaphylaxis. The following are suggested equipment and medications for the management of systemic immunotherapy reactions. Modifications of this suggested list might be based on anticipated emergency medical services’ response time and physician’s airway management skills.[29]

• Stethoscope and sphygmomanometer

• Tourniquet, syringes, hypodermic needles, and intravenous catheters (eg, 14-18 gauge)

• Aqueous epinephrine HCL 1:1,000 weight/volume

• Equipment to administer oxygen by mask

• Intravenous fluid setup

• Antihistamine for injection (second-line agents for anaphylaxis, but H1 and H2 antihistamines work better together than either one alone)

• Corticosteroids for intramuscular or intravenous injection (second-line agents for anaphylaxis)

• Equipment to maintain an airway appropriate for the supervising physician’s expertise and skill

• Glucagon kit available for patients receiving beta-blockers

For more information, see the article Anaphylaxis.

With appropriate evaluation and management of allergy, including avoidance, environmental control, pharmacotherapy, and immunotherapy, the long-term results of allergy treatment are very positive. Many patients enjoy the benefits of long-lasting symptom control and improvement in quality of life.

Allergen immunotherapy has been clinically demonstrated to provide long-term clinical benefits, including symptomatic disease remission and a reduction in allergic disease progression from rhinitis to asthma.[1] A meta-analysis by Farraia et al showed a strong effect of allergen immunotherapy in preventing the onset of asthma in children who completed 3 years of treatment and in monosensitized patients.[30] Allergen immunotherapy has also demonstrated long-term effectiveness in symptom reduction more than 3 years following treatment cessation and has prevented the development of new sensitizations in children.

Allergen immunotherapy results in a long-term reduction in serum allergen-specific IgE levels. Significant reductions in the early-phase response have also been demonstrated.[9, 10, 11, 8, 12]

Research is ongoing regarding the comparative efficacy of sublingual immunotherapy with that of subcutaneous immunotherapy.

Local nasal immunotherapy (LNIT) is being investigated as an alternative noninjection method of immunotherapy for allergic rhinitis. A meta-analysis by Kasemsuk et al found that LNIT improved clinical symptoms, reduced medication use, and increased the nasal provocation threshold.[31]

Refer patients to the Web sites of the American Academy of Allergy Asthma & Immunology or America's College of Allergy for allergy and dustproofing information.

Companies including National Allergy Supply and the Allergies Buyers Club have information and products available for purchase to augment allergy control and treatment.

Patient Instructions

Prior to each allergy shot, it is recommended that the health care provider confirm that no reaction occurred during the preceding shot, the patient has begun no new medications, (particularly beta-blockers), and that asthma, if present, is stable via peak flow measurement.

Elements of Informed Consent

Any medication (including beta-blockers) or health contraindications (eg, loss of asthma control) should be identified.

Duration of treatment and symptom control should be discussed.

Patients who become pregnant while on immunotherapy may continue treatment; however, commencing immunotherapy in pregnant women is not advisable. Some authors do not advance immunotherapy in pregnant women until the postnatal period.[29]

Subcutaneous immunotherapy should be initiated only in patients willing and able to comply with weekly injections for a year or longer. Once maintenance is reached, the injection regimen may become less frequent; however, several years’ duration is commonly required for clinical efficacy.

Sublingual immunotherapy is appropriate for patients who are unable to commit to weekly injections or those who do not want injections.

Interestingly, a 2013 study by Kiel et al demonstrated that long-term adherence favored subcutaneous immunotherapy over sublingual immunotherapy.[32]

Choosing antigens to treat with immunotherapy

Careful consideration must be given to the timing and location of symptoms when choosing antigens to treat. For example, a patient with spring-only symptoms who allergic to trees and ragweed may not require immunotherapy for ragweed. A patient with symptoms that occur only when visiting homes where cats live may not require treatment for their pollen sensitivities. Testing should be based on a patient’s specific allergen exposure.[33]

Cross-reactivity

Several inhalant classes contain different species that are cross-reactive, so treating with one of the antigens is sufficient. Only one of the pooid grasses, for example, (most often timothy) is usually included in a patient’s mix. Similarly, the Olive-Ash family may not require treatment of all antigens.

The existence of cross-reactivity to panallergens such as profilins, similar in many species but not the actual instigators of allergic reactions, could lead to unnecessary inclusion of these inhalant antigens.

Starting dose of immunotherapy

The starting dose can be (1) the same dilute dose for all antigens, (2) based on backwards calculation from the target maintenance dose, or (3) based on semiquantitative testing such a intradermal dilutional testing or radioallergosorbent test (RAST) or ImmunoCAP (ICAP) classes.

Equivalent initial dose for all treated antigens

Most allergists/immunologists and many otolaryngic allergists use an initial dose equivalent for all treated antigens. Using either 5- or 10-fold dilutions of the antigen concentration supplied by the manufacturer, 4-6 vials of increasingly weaker antigen are prepared. Treatment is started with a very small dose from the weakest vial, works up to a larger dose from this vial, and continues to a very weak dose from the next-strongest vial. Many allergists modify the dose increase upon a significant local reaction, some evidence has shown that this is unnecessary.[34] A reasonable starting dose for most patients is 0.5 mL of a w/v concentration of 1:200,000-500,000.

Quantitative-based initial dose

Some otolaryngic allergists use a quantitative-based initial dose. Intradermal skin testing is performed with increasing concentrations of each antigen, beginning with a sixth 5-fold dilution from manufacturer’s concentrate (typically 1:20 w/v), yielding a 1:312,500 w/v concentration. The concentration at which the patient first develops at least a 7-mm wheal is used as the beginning treatment dose. For example, a fourth 5-fold dilution from concentrate would give a concentration of 1:12,500. If this is the point at which the first clinically significant skin reaction occurs, this is the concentration of this antigen used in the initial treatment vial.

The theoretical advantage of this approach is that antigens to which the patient is more sensitive are started at a lower dose and those to which the patient is less sensitive are started at a higher dose. Theoretically, this minimizes problems with escalation caused by large local or systemic reactions to the most sensitive antigen. There have been no head-to-head studies comparing this technique to the traditional approach.

Mixing inhalant immunotherapy vials

When mixing a vial for immunotherapy, if the final desired dose is the starting point, this is figured for each antigen in the treatment vial. In general, this will be 5-12 µg per dose. Since beginning immunotherapy with the desired final concentration would likely result in significant systemic reactions, dilutions are prepared from this concentration to begin with a very weak concentration. This is gradually increased as tolerated by the patient’s body until the desired final treatment dose is reached.

Some insect and fungal antigens contain high levels of protease, which can potentially degrade pollen proteins, causing more rapid than expected loss of bioactivity. Some physicians recommend always separating insect and fungal antigens into a different vial from pollen antigens to prevent this happening.

Vial test

Some practitioners suggest that a useful safety measure is injecting a small dose of each new vial intradermally, where there are more reactive cells. The development of an unexpectedly large wheal from this technique may suggest that it may be prudent to dilute this vial further before beginning usual subcutaneous injections.

Using this technique, a 4-mm intradermal wheal is placed and observed for 10-20 minutes. If the resultant wheal is smaller than 13 mm, the first dose is given. If the wheal is 13 mm, retest in a few days. If the wheal increases to larger than 13 mm, consider diluting the vial. If using 1:5 dilutions, this is performed by taking 1 mL from it and adding it to 4 mL of diluent. This new dilution is then vial tested.

See Complication Prevention.

Should anaphylaxis to immunotherapy occur, the management in an inpatient setting may be appropriate.

The treatments described above may be used to provide control of allergic symptomology. A history and physical examination should be performed at least annually by treating physicians once the patient has achieved maintenance on immunotherapy. While not dogma, some physicians recommend that patients have up–to-date EpiPens for use as needed, especially if the patients are administering their own allergy shots at home.

Immunotherapy via the subcutaneous or sublingual route is an effective treatment of allergic symptoms.

The typical duration of immunotherapy is at least 3 years; some patients require a more lengthy treatment period.[35, 36, 37, 38, 39, 40]

Subcutaneous immunotherapy should be initiated only in patients willing and able to comply with weekly injections for a year or longer. Once maintenance is reached, the injection regimen may become less frequent; however, several years’ duration is commonly required for clinical efficacy.

Sublingual immunotherapy is appropriate for patients who are unable to commit to weekly injections or those who do not want injections.

The initial immunotherapy dose is often 0.05 mL of allergy vaccine. Escalation of immunotherapy proceeds weekly by giving 0.05 mL more antigen than the previous injection. It is generally recommended that the antigen dose be reduced by 50% when a new vial is begun.

Immunotherapy escalation schedules

When the volume of the dose reaches 0.50 mL, the next vial should begin with an increase in the concentration of the antigen.

There are multiple escalation schedules. Most common is a weekly increase of 0.05 to 0.1 mL of allergy vaccine, up to a high volume of 0.5 mL, and then to the smallest dose from the next strongest vial, until the maintenance dose is reached.

Rush immunotherapy

Rush immunotherapy may be appropriate in properly selected patients. This regimen begins with 0.5-mL injections and advances weekly by 0.1-mL volumes instead of 0.05 mL.

However, while maintenance is reached more rapidly, the risk of anaphylaxis is greater.

Multiple schedules have been described in the literature. These methods may be most appropriate for stinging insect allergy if the risk of another sting is high.

Immunotherapy maintenance

Immunotherapy maintenance[41, 42] aims to achieve long-lasting symptom relief from aeroallergens and other provoking antigens. The goal is to establish a steady-state dose that provides immediate and long-lasting immune system alteration in response to allergen and keeps a patient asymptomatic. As described above, on a cellular level, the goal is to decrease antigen-specific IgE and increase the levels of antigen-specific IgG4 antibody.[43, 44] The clinical relevance of changes in IgG4 are unclear and are currently under investigation. This alteration tends to occur during escalation and after symptomatic relief is achieved.

Managing physicians may allow selected patients who have well-controlled allergic symptoms and have achieved maintenance on immunotherapy to administer their shots at home. This should be performed with someone else in the home. The patient must have a current EpiPen. As noted by recent guidelines, home administration of immunotherapy should be considered only in “rare and exceptional cases when allergen immunotherapy cannot be administered in a medical facility and withholding this therapy would result in a serious detriment to the patient’s health (eg, VIT for a patient living in a remote area). Careful consideration of potential benefits and risks of at-home administration of allergen immunotherapy should be made on an individual basis.”[29]

Once maintenance has been achieved for a period, the shot regimen may change from weekly to every other week or every third week. This may be appropriate if, during the schedule change, the patient remains symptom-free and without local reaction. If the patient notices that symptoms increase with a lengthened period between shots, the interval is decreased.

Treatment for 3 years or longer may be required to achieve adequate long-lasting effects.

Sublingual Immunotherapy

The most common technique is to hold the allergy vaccine under the tongue for 2 minutes and then to swallow it. Patients should note any oral itching, swelling, wheezing, rashes, or esophageal or gastrointestinal distress and discuss it with their physician.

Maintenance treatment for 3 years or longer may be required to achieve adequate long-lasting effects.

In April 2014, the FDA approved a sublingual tablet (Oralair) consisting of 5 calibrated grass pollen extracts. It contains Perennial Ryegrass (Lolium perenne), Kentucky bluegrass (Poa pratensis), Timothy grass (Phleum pratense), Orchard grass (Dactylis glomerata), and Sweet Vernal grass (Anthoxanthum odoratum).[45] The Oralair SL tablet needs to be administered 4 months prior to the season for the specific allergen.

A second sublingual tablet (Grastek) for Timothy grass was also approved by the FDA in April 2014 for adults and children aged 5 years or older. It should be administered at least 12 weeks before the start of the grass pollen season. The efficacy and safety in North America was established in a large study (n=1500) of adults and children aged 5-65 years. Results showed a 23% improvement of symptoms in the entire grass pollen season.[46]

A third sublingual immunotherapy tablet for ragweed (Ragwitek) was also approved in April 2014 for adults aged 18 years or older. The effectiveness studies included about 760 patients. Phase 3 clinical trials showed that the tablet reduced rhinoconjunctivitis symptoms over the entire season by 27-43% compared with placebo.[47, 48]

A sublingual (SL) house dust mite (HDM) immunotherapy (Odactra) was approved by the FDA in 2017. It is a standardized allergen extract indicated as daily SL immunotherapy for allergic rhinitis, with or without conjunctivitis, confirmed by in vitro testing for IgE antibodies to Dermatophagoides farinae or Dermatophagoides pteronyssinus house dust mites, or skin testing to licensed house dust mite allergen extracts.

The first dose must be given in a healthcare setting under the supervision of a physician with experience in diagnosis and treatment of allergic diseases. Patient monitoring for signs or symptoms of a severe systemic or local allergic reaction is required following administration. Life-threatening allergic reactions is described in a boxed warning within the prescribing information. The boxed warning also includes the need to prescribe autoinjectable epinephrine for the patient to have while using HDM immunotherapy.

Approval was based on a double-blind, multicenter trial (n = 1482) in adolescents and adults with HDM allergic rhinitis with or without conjunctivitis (AR/C). Over a 52-week period, HDM immunotherapy improved rhinoconjunctivitis score and visual analog scale-assessed AR/C symptoms (P < 0.001).[49]

A double-blind, randomized study by Virchow et al evaluated the efficacy of the house dust mite sublingual allergen immunotherapy tablet (SLIT) by measuring the time to the first moderate or severe asthma exacerbation during an inhaled corticosteroid reduction period in 693 patients. The study found that the two groups that received doses of the tablet had significantly reduced risk (absolute reduction at 6 months of 9 to 10 percentage points) of a moderate or severe asthma exacerbation compared with the placebo group. It should be noted however, that there was no significant difference for change in asthma control questionnaire or asthma quality-of-life questionnaire with active treatment. Although there were no reports of severe systemic allergic reactions, there were treatment-related adverse events commonly seen with SLIT to dust mite.[50, 51]