Guidelines for practice of allergen immunotherapy in India: 2017-An update

SN Gaur; Raj Kumar; AB Singh; MK Agarwal; Naveen Arora

doi:10.4103/ijaai.ijaai_10_17

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GUIDELINES

Year : 2017 | Volume : 31 | Issue : 1 | Page : 3-33

Guidelines for practice of allergen immunotherapy in India: 2017-An update

SN Gaur, Raj Kumar, AB Singh, MK Agarwal, Naveen Arora
Indian College of Allergy, Asthma and Immunology, V. P. Chest Institute, University of Delhi, New Delhi, India

Date of Web Publication

12-May-2017

Correspondence Address:
S N Gaur
Director – Professor and Head, Department of Pulmonary Medicine, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi - 110007
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/ijaai.ijaai_10_17

Abstract

The practice of Allergy and Immunotherapy is not streamlined in our country and there were no guidelines till we published in 2009 in IJAAI. The guidelines are updated now incorporating the additional information after 2009. The purpose of bringing out these guidelines was to maintain the uniformity in the methods of diagnosis and management i.e. Immunotherapy in the country. Because of different soil conditions, temperature, different allergens, different seasonal variations etc, it was the felt the need to have separate guidelines for India, although such guidelines are available from other organisations. These guidelines are based on available guidelines with modifications/alterations at appropriate places keeping in mind the situation in our country.

Keywords: Allergen, guideline, immunotherapy

How to cite this article:
Gaur S N, Kumar R, Singh A B, Agarwal M K, Arora N. Guidelines for practice of allergen immunotherapy in India: 2017-An update. Indian J Allergy Asthma Immunol 2017;31:3-33

How to cite this URL:
Gaur S N, Kumar R, Singh A B, Agarwal M K, Arora N. Guidelines for practice of allergen immunotherapy in India: 2017-An update. Indian J Allergy Asthma Immunol [serial online] 2017 [cited 2023 Mar 27];31:3-33. Available from: https://www.ijaai.in/text.asp?2017/31/1/3/206193

Introduction

Allergen immunotherapy (AIT) is an immunomodulatory method for the treatment of immunoglobulin E (IgE)-mediated allergic diseases to control the symptoms and decrease the sensitivity toward allergen(s) by giving sequentially increasing dose of antigen(s) to induce a shift of the immunological response from TH2 to TH1. Numerous terms have been used to describe AIT for treating allergy, including allergen-specific immunotherapy (IT), specific IT, and other terms such as hyposensitization and desensitization.^[1] The term AIT is used most recently to refer to the class of therapies that aim to induce immune tolerance to allergens. AIT is a therapy with disease-modifying effects and is currently used for the treatment of allergic rhinitis, rhinoconjunctivitis, allergic asthma, and venom hypersensitivity. It is the only method to prevent the onset/progression of asthma in patients suffering from allergic rhinitis/rhinoconjunctivitis. AIT can be administered through different routes (subcutaneous, sublingual, oral, nasal, bronchial, and lymphatic), but currently, only subcutaneous IT (SCIT) and sublingual IT (SLIT) have sufficient evidence and therefore are routinely used.^[1],[2],[3]

Following the international regulations, which are also relevant for India, the practice of AIT should be allowed only to those physicians who have obtained specialized training in allergy and AIT and to be practiced at a place where facilities of managing anaphylaxis are available.

Guidelines for AIT are available in Western/developed countries,^{[1],[2],[3],[4],[5]} but a separate guideline focusing on India is also necessitated due to a multitude of factors. This 2017 update by the Indian College of Allergy, Asthma, and Applied Immunology (ICAAI) has been prepared to review the recent data and update the guidelines published in 2009.^[6] The aim of the current guidelines is to provide clinicians comprehensive recommendations on the use of AIT in their daily practice.

Mechanism of Action

Initially, it was presumed that by giving low doses of same antigen, the immune system produces IgG antibodies (blocking antibodies) instead of IgE antibodies and thus consumes the antigens, resulting in less number of IgE molecules available to produce allergic reaction. However, the changes in clinical parameters post-IT did not always correlate with the changes in IgG or IgE levels. It is now well established with a number of evidence that AIT produces a shift of TH2 response toward TH1. This brings the reduction in release of inflammatory mediators, specific IgE (sIgE) levels, and allergen-specific airway hyperresponsiveness apart from producing clinical improvement. There is an increase in specific IgG levels after AIT. However, initial increase in IgG4 level indicates poor prognosis but that of IgG1 means a better prognosis. AIT induces a decrease in interleukin-4 (IL-4) and IL-5 production by CD4⁺ TH2 cells and a shift toward increased interferon gamma (IFN-γ) production by TH1 cells. Activation of TH1 subset is associated with the development of cell-mediated immunity, essential for protective immune response against the development of allergy/asthma. AIT acts by modifying TH4⁺ T-cell responses either by immune deviation, T-cell anergy, or both. Further, a subtype of T-cells with immunosuppressive function and cytokines profiles distinct from their TH1 and TH2 cells, termed regulation/suppressor T-cell, have been described. T-regulatory (Treg) cells producing IL-10 and possibly transforming-growth-factor beta (TGF-β), CD4⁺ CD25⁺ T-cells, and TH3 cells play a major role in the inhibition of allergic disorders. The expression of FOXP3 on CD4⁺ CD25⁺ T-cells has also been demonstrated to correlate with the suppressive capacity of Treg cells and clinical efficacy following AIT. [Figure 1] depicts the mechanism of action of AIT.^[7]

Figure 1: Mechanism of AIT

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Selection of Patients

The success of AIT depends on proper selection of patients, allergens, doses, quality of allergens, and compliance to the treatment. AIT results may reflect failure if done by an untrained person. Unnecessary testing, wrong prescription of IT, and taking advantage of psychology of patient can lead to adverse reputation in AIT practice.

AIT has proved useful in patients with IgE-mediated diseases such as allergic rhinitis, asthma, and insect sting hypersensitivity. It should be considered in a patient who had history of systemic anaphylaxis reaction after an insect sting and have documented IgE sensitivity to specific venom, and there is a likelihood of future exposure to the insect. AIT can be lifesaving in such cases with appropriate antigen. Patients with atopic dermatitis (AD) due to the aeroallergen house dust mites (HDMs) may also be an appropriate candidates for AIT [Table 1].^{[1],[2],[3],[5]}

Table 1: Indications for allergen immunotherapy

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Patients of allergic rhinitis, of asthma, and with history of symptoms after natural exposure to the allergen demonstrated sIgE antibodies against the offending allergens. The allergy is assessed by clinical history, skin tests, and radioallergosorbent test (RAST) or enzyme linked immunosorbent assay (ELISA). AIT is prescribed for patients ≥5 years with no limit on the upper age, with symptoms interfering with their routine work or school performance, causing sleep disturbances, and quality of life (QoL). Patients who failed to avoid allergen exposure in spite of all efforts or had no response to allergen avoidance had poor response to drugs or tired of taking drugs or developed adverse reactions to medicines are most suitable candidates for AIT. The patients selected must assure long-term compliance for the therapy and should not have contraindications for AIT [Table 2].^[8]

Table 2: Contraindications for allergen immunotherapy

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A shorter disease duration and compliance to AIT improves clinical outcomes. [Table 3] discusses additional factors associated with favorable outcomes.^[5]

Table 3: Factors that increase the clinical efficacy of allergen immunotherapy^a

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Selection of allergens

The local flora/airborne pollens change approximately every 200 km distance in India. The soil conditions along with environment of the place may affect the protein content as well as the antigenicity of the allergens. The urban and rural setup as well as the coastal or hilly climate affects the type or antigenicity of the atmospheric pollens in our country. Currently, more data need to be generated to understand the interplay between the above-mentioned factors and allergenic properties. It is essential to select the antigens for testing in a patient based on the above points and confirming the history of exposure. Besides, it is important to have the knowledge about the geographical habitat, occupation/residence of the patient, and also the precipitating factors for his/her allergic symptoms.

A document on aeroallergens (pollens) in different parts of the country has been published ^[9] and can be consulted to frame the testing kit for patients residing in respective area. Physicians/allergologists are also required to consult local aerobiological studies and studies evaluating the sensitization patterns ^{[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33]} published in relevant journals for the prevalence of airborne pollens, fungi, insects, and mite allergens. They can consult the researchers at their nearest botany, plant pathology, and entomology departments or attend training courses in identification of allergens. Relevant allergens are included in Indian allergen manufacturer's list, which are mostly common throughout the country. Some of the allergenically important pollens are Prosopis juliflora, Ricinus communis, Chenopodium album, Cynodon dactylon, Artemisia species, Alnus nitida, Amaranthus spinosus, Parthenium hysterophorus, Cassia siamea, and members of Poaceae.^[22] While numerous references are available from the different geographical zones of India, limited evidence is available from the Himalayan area.^[13],[34] Among the Himalaya pollen, a high incidence of skin sensitivity was observed to pollen antigens of Cedrus deodara, Mallotus philippensis, and Quercus incana in patients of Chandigarh residing in the hills and foothills of the Himalayas while A. nitida, Betula utilis, and C. deodara were important sensitizers in New Delhi patients. Furthermore, the skin sensitization pattern against these pollens was in accordance with the level of exposure to these pollen of the subjects residing in that part of the country.^[13] Two HDM species, namely Dermatophagoides pteronyssinus and Dermatophagoides farinae, are predominant in regions with high humidity, especially in coastal areas. Blomia tropicalis is another important mite species found to be prevalent in tropical countries and it is found to be prevalent in about 15% of Indian patients.^[35] Another mite species Acarus siro and Tyrophagus specieshave also been found to be present in studies published from India.^{[36],[37],[38]} In some patients, new antigens for testing may be required decided on individual basis after surveying patient's environment.

Studies focusing on food sensitizations in India have demonstrated the relevance of the following food allergens in patients with respiratory allergies: Rice, black gram, lentils, citrus fruits, peanut, banana, fish, soybean, chicken, wheat, etc., In a study conducted in New Delhi, patients aged 12–62 years were screened for food allergies using standard questionnaire and skin prick-test (SPT). sIgE level was determined by ELISA, and allergy was established by blinded food challenges. In this study, food allergy is estimated to be 4.5% in adolescents and adults with asthma, rhinitis, or both. Rice, citrus fruits, black gram, and banana were identified as major allergens for inducing allergic symptoms.^[39] Furthermore, Indian-specific data suggest that severe SPT reactions (4 mm or above) and sIgE, 6.9 ng/ml to rice are associated with positive blinded food challenge with clinical symptoms.^[40] Results from the recently published EuroPrevall-INCO study which was conducted in Karnataka, South India, demonstrated a high level of sensitization (26.5%) for most of the foods in the general population, higher than that observed among adults in Europe. The highest prevalence of sensitization to individual foods was observed for shrimp and sesame and was above 13%. However, the prevalence of probable food allergy (self-reports of adverse symptoms after the consumption of food and sIgE to the same food) was 1.2%, which was mainly accounted for cow's milk (0.5%) and apple (0.5%) with very few cases, with probable food allergy to egg and banana (0.05% each) and to sesame, wheat, and tomato (0.02% each).^[41]

Relevant allergens are major contributors to the safety and efficacy of the allergenic extracts used for AIT. Most of the available data address HDMs and selected pollens, whereas less is known about the efficacy and safety of mold, animal epithelia, venom, and cockroach [Table 4].^[3],[42]

Table 4: Allergens of proven efficacy in allergen immunotherapy trials globally

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Allergen extracts which have been evaluated in Indian studies include HDMs, pollen, horse dander, insects (cockroach, mosquito, and housefly), and mixes of allergen extracts.

Diagnostic Tests for Detecting Sensitizing Allergen(S)

For AIT of patients with IgE-mediated respiratory allergic disorders, identification of specific causative allergens is of paramount importance. Patient's history and clinical examination are the primary modalities for identifying an allergic etiology and identifying the likely allergens responsible for the allergic symptoms. The following in vivo and in vitro diagnostic tests are recommended ^{[43],[44],[45]} and commonly used:

In vivo tests

Skin tests (prick and intradermal)^{[46],[47],[48]}
Mucosal challenge tests (bronchial ^[49] and nasal ^[50] challenge, double-blind placebo-controlled food challenge ^[51]).

In vitro tests

It is used for the quantification of total serum IgE/allergen-sIgE levels.

RAST ^[52],[53]
ELISA
Multi-allergen screening assays.

In vivo tests

Skin tests

Skin tests with inhalant allergens are simple and effective method for the identification of causative allergens. They are the most accurate diagnostic procedures for demonstrating that a specific allergen has induced an IgE antibody response and are regarded as the gold standard for the detection of IgE antibodies.^[54] Skin tests are convenient, simple, biologically relevant, reproducible, easy and rapid to perform, with low cost and high sensitivity. Studies indicate that skin testing might be more sensitive than in vitro tests in detecting allergen-sIgE.^{[55],[56],[57],[58],[59],[60]} SPTs and intradermal tests vary in sensitivity and specificity, which depends on multiple factors such as concentration and quality of allergen solution.

Preparation of high-quality allergen extracts is essential for the diagnosis and AIT of allergic disorders. Standardized allergen extracts should be utilized as unstandardized extracts have large batch-to-batch variability (10–>100 times) and thus may have variability in the test results.^[61] Recently, biological unit (BU) – used mostly in Europe, and bioequivalent allergen unit (BAU) – used mostly in the US, have come to be widely used on standardized products. While the BU is an in vivo standardization unit based on the SPT response compared with histamine, the BAU is based on intradermal skin tests. Furthermore, the global guidelines also recommend maintenance of an in-house reference standard, with which all the production batches should be compared using in vitro techniques of standardization.

A positive control (histamine diphosphate/dihydrochloride) is always used to ensure (i) that the patient is suitable for the performance of skin tests and (ii) is not taking any medication (s) which may suppress the cutaneous response to injected allergen extracts. Similarly, test with the diluent used to prepare/preserve the allergen extracts is also performed as negative control to rule out the possibility of getting false positive skin response due to dermographism or traumatic reactivity induced by skin test device.^[62]

Skin prick test

The position papers on skin tests by the European Academy of Allergy and Clinical Immunology (EAACI) and the US Joint Council of Allergy, Asthma and Immunology (American Academy of Allergy, Asthma and Immunology [AAAAI], ACAAI) state that properly performed prick test is a most convenient for better clinical correlation and are economical.^[62],[63] In addition, the World Allergy Organization (WAO) has mentioned that SPT is the best screening method for detecting sIgE antibodies.^[54] They are highly reproducible when carried out by trained individuals. SPTs are minimally invasive, have high specificity, and have a lower rate of systemic effects as compared to the intradermal tests. SPT is the gold standard diagnostic method to detect allergen sensitization.

Medicines to avoid before the skin prick tests

Certain medicines are known to decrease skin reactivity, leading to false negative skin tests. Clinicians should be aware of the medicines that could interfere with allergy testing and should counsel their patients to avoid these to achieve an appropriate diagnosis [Table 5].^[62],[64]

Table 5: Medicines having a suppressant effect on the skin prick test

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Medicines which do not have a suppressant effect on the SPT include intranasal antihistamines, nasal and inhaled corticosteroids, leukotriene receptor antagonists (montelukast), angiotensin-converting enzyme-inhibitors, β-agonists, cyclosporine, H₂-blocker, theophylline, selective serotonin reuptake inhibitors, and selective norepinephrine reuptake inhibitors.

Intradermal test

In Western countries, allergen extract solutions for intradermal tests have been recommended to be 100-fold or 1000-fold dilution of the concentration used for prick test. However, in India, 25–50-fold dilution of the concentration used for prick tests (1:10/1:20 weight/volume [w/v]), i.e., 1:500 w/v, has been found suitable for intradermal tests.^[46],[48] Intradermal tests are more sensitive than SPT testing and thus may provide more false positive results than SPT. Furthermore, they possess a greater risk of systemic reactions (SRs) than SPT testing. Therefore, the intradermal tests are generally used when percutaneous tests are negative despite an adequate history of exposure and symptoms.^[65]

Mucosal challenge tests

Mucosal challenge tests with allergen extracts, both bronchial challenge and nasal provocation tests (NPTs), are of limited clinical value.^[49],[50] These tests are mostly used for research purposes as they do not give any significant clinical information, in addition to that provided by properly taken clinical history and carefully performed and graded skin tests.

The in vivo methods are summarized below for reference:

Skin tests are followed commonly for allergy diagnosis with allergen extracts. The SPT is most convenient for better clinical correlation and is a least expensive in vivo diagnostic test
Patient having skin diseases such as eczema, leukoderma, dermographism, severe dermatitis, and any other chronic skin disease is not fit for skin testing, and in case of fever, the test is postponed till the patient becomes normal
For SPT, the allergens are tested in 1:10 or 1:20 w/v dilution, and in intradermal test, antigens are injected intradermally in 1:500 w/v dilution
Antigens are administered in the volar aspect of the arm or on the back of the patient with a distance of 5 cm (intradermal) or 3 cm (prick) in between the two tests
Globally, the wheal diameter is measured after 15–20 min and reported in “mm.” A skin reaction of ≥3 mm than that produced by the negative control on the SPT is considered as a positive reaction. This is done to maintain objective assessments of the SPT responses ^[62],[63]
Qualitative scoring (0–4+; 0 or +) is no longer used by many clinicians because of marked interphysician variability in scoring and interpretation of this method
The global guidelines do not support the use of grading the skin response. However, in India, some clinicians still use the grading system for documenting skin reactions. Grading of skin reaction is done after 15–20 min in comparison with negative control (phosphate buffered saline [PBS]) and positive control (histamine diphosphate/dihydrochloride). For grading of allergic reaction (skin tests), the criteria given in Tables 6 and 7 can be followed [Table 6] and [Table 7].^{[46],[53],[66]}

The significance of allergen for considering AIT is considered only if the reaction is equal to or more than the positive control.

Table 6: Grading for the skin prick test

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Table 7: Grading for the intradermal test

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Physician should be available at the time of skin testing to take care of any adverse reaction
In case of high sensitivity (history), skin tests are performed with diluted antigen extracts
In case of doubtful reaction, a repeat skin test is performed to confirm the reaction
Provocation tests with allergen are recommended only at the institution level and are mainly done for research purposes.

In vitro tests

Most commonly used in vitro diagnostic tests ^[53] for the estimation of total IgE and allergen-sIgE levels in the sera of allergic patients are radio/enzyme immunoassays. The basic principle remains the same, in which a solid phase allergen/antibody binds with primary antibody which is further detected using a radio/enzyme-labeled secondary antibody. The binding signal is converted to a quantitative measurement of concentration using a standard curve, in which one reactant is added in known amounts.

To establish atopic status of the patient, total serum IgE levels are measured.^[45] However, the measurement raised IgE levels are also found in some nonatopic individuals and in patients suffering with various nonallergic diseases. An Indian study has also concluded that “the IgE levels in Indian allergic patients is significantly related to atopy; however, due to wide overlap of IgE levels in patients and healthy subjects, its diagnostic significance in Indian population seems to be limited.”^[67]

Measurement of allergen-sIgE levels gives reliable information about patients' clinical sensitivity to various aeroallergens. For this purpose, kits based on immunoenzymetric techniques commercially available can be used. Multiallergen screens are useful to support a more extensive clinical and immunologic investigation for allergic diseases.

In vitro tests are considered as a backup tool to SPT and should be utilized in cases when the SPT cannot be performed.

Quality assurance is very important for all these in vitro diagnostic tests. In the USA, external proficiency surveys are conducted in selected laboratories for checking uniformity of results using reference samples. In India, there is an urgent need to conduct such surveys to establish indigenous quality control standards for the measurement of allergen-sIgE levels.

AIT should not be given only on the basis of the serological tests.In vitro tests may be used only as a supportive test or in situ ations, in which skin testing is not possible.

Types of Allergen Immunotherapy

Subcutaneous Immunotherapy

The subcutaneous route has been the commonly used method of administration of AIT.

Types of allergen extracts

In India, native extracts available as aqueous preparations are used for SCIT. These allergen extracts are prepared by aqueous extraction of allergenic materials obtained from natural sources. The composition and biologic properties may be influenced by the quality and purity of the source material, as well as their processing, extraction, and storage conditions. In addition to aqueous extracts, which are commonly used, depot extracts are primarily used in Europe for SCIT. In Europe, allergens or newer hypoallergenic preparations are physically adsorbed to a carrier, such as aluminum hydroxide (most common), tyrosine, or calcium phosphate. The concept of hypoallergenic preparations is that they possess less reactive B-cell epitopes and thus reduce IgE binding, while their T-cell epitopes and their immunogenic effect remain unaltered.^[68],[69] In Europe, these hypoallergenic preparations comprise up to 50% of the SCIT prescriptions.^[70] Numerous studies have provided clinical efficacy and safety of the allergen extracts. Advantages of hypoallergenic preparations are lesser SRs, shorter dose build-up phase, and less frequent dosing.

Administration regimens

Conventional regimen

Currently, in India, only aqueous extracts are available. In most of the cases, AIT is started with 1:5000 w/v diluted antigen and the injections are given two times a week starting from and increased by 0.1 ml in every injections. The injections are given subcutaneously with graduated syringe or insulin syringe. The idea is to achieve the highest maintenance dose, i.e., 1:50 – one time a month, 1.0 ml. Usually, the maintenance dose is between 0.5 and 1.0 ml of 1:50 dilution. In cases showing high skin sensitivity with local reaction (LR)/SR after initiation (1:5000 w/v) of AIT, it is rescheduled/started with higher dilution, i.e., 1:50,000 w/v or even higher dilution, and the first injection is administered in the hospital/clinic having facilities to manage anaphylaxis.

Fewer buildup injections are possible with the depot and hypoallergenic formulations. Furthermore, the maintenance doses may be given in a period of 4–8 weeks, thus reducing the burden of repeated injections. Randomized trials with accelerated up-dosing of hypoallergenic preparation for pollen have also been recently conducted, in which the maintenance dose is achieved in 4 weeks with safety and tolerability profiles comparable to the conventional dose escalation.

Rush immunotherapy

The advantage of rush schedule is that patients can attain the maintenance dose more quickly. Schedule for rush IT entails administering multiple injection in a row preferably in a hospital setup. Schedules using eight injections over 3 days or 8 injections in a single day have been published.^[71] However, these protocols need further investigation in terms of risk and benefit ratio to patient.

Cluster immunotherapy

The starting dose is similar to those of perennial AIT regimen. Here, weekly visits are necessary because, at each visit, more than one injection is given at a small interval between injections, varying from 30 min to 2 h. After the maintenance dose is reached in approximately 2 months, interval between visits is increased. The cluster regimen is advantageous to the patients who reside at a significant distance from a physician. There are similar efficacy and immunological changes in cluster regimen as observed with the perennial IT in various studies.^[72] However, the initial doses are required to be given in a hospital set up able to manage emergencies associated with this form of therapy. Cluster schedule with hypoallergenic mite-SCIT has also been developed and is found to be safe and well-tolerated in routine clinical practice.

Sublingual immunotherapy

The sublingual route has attracted the greatest interest in recent years as shown by the number of double-blind, placebo-controlled trials and the fact that SLIT has spread widely in some countries in Europe. However, further studies are needed to define the most appropriate dosage, the efficacy in pediatric patients, and to evaluate the magnitude of efficacy compared to other available treatments.^{[73],[74],[75],[76]}

In contrast to the subcutaneous route, SLIT requires a much higher amount of antigen to achieve clinical efficacy. On an average, SLIT requires at least 50–100 times more allergen content than SCIT to be efficacious, and consequently, low-dose SLIT is generally ineffective.^[77] Furthermore, in comparison with SCIT (which is standardized in regimens and protocols), SLIT is affected by numerous variables [Table 8]. It can be administered as drops, mono-dose vials, or tablets and with variable timings and doses. In particular, the maintenance dose is strictly dependent on the method of standardization, which varies from one manufacturer to another.^[78]

Table 8: Evidence of head-to-head comparison of subcutaneous versus sublingual immunotherapy

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In addition to above-mentioned points of variability in the doses, SLIT has also been clinically effective only for a limited number of allergens.

SLIT is currently not approved in India but is under consideration of the drug regulatory authority.

Other routes

Bronchial immunotherapy

A limited number of clinical trials have been carried out using this route of administration.^[79],[80] The results obtained were unimpressive in terms of efficacy, and the bronchospasm was induced in many of the patients treated. Therefore, this route of administration has been abandoned in view of an unfavorable risk–benefit ratio.

Oral immunotherapy

Although a greater number of clinical trials with a suitable design ^[81] have been carried out using this route of administration, a few of them achieved an acceptable level of clinical efficacy.^[82],[83] In some trials,^[84],[85] the effect was no better than that of placebo. Furthermore, adverse events including abdominal pain, vomiting, and diarrhea were recorded in some studies.^[85],[86] The present results do not support the oral route as an effective alternative.^[87]

Nasal immunotherapy

Twenty-two studies of intranasal administered AIT have been evaluated.^[88] Sixteen used a double-blind, placebo-controlled design. Most of these trials demonstrated significant clinical efficacy in allergic rhinitis. The results are encouraging, but nasal AIT seems to be a treatment for allergic rhinitis only. Some studies also reported local adverse effects.^[89],[90] The only study addressing long-term efficacy demonstrated no sustained effect, following discontinuation of the treatment.^[91] There are no data on the possible preventive capacity.

Additional approaches to AIT under active investigation include epicutaneous and intralymphatic administration. A few clinical trials with intralymphatic route have indicated that this route is efficacious and safe with a limited number of injections.^[78]

Duration of Allergen Immunotherapy

AIT is generally administered for 3–5 years; the duration and decision to discontinue it must be individualized. Some patients may require longer periods of treatment. It is difficult to predict that how long patients will experience symptomatic relief following discontinuation of AIT. However, prolonged remission of symptoms after discontinuation has been documented in prospective studies with grass pollen SCIT for allergic rhinitis and HDM SCIT for asthmatic patients.^[92],[93]

Clinical benefits which are ongoing have been documented 12 years after discontinuation of AIT as compared to pharmacotherapy only (please see the section on “Preventive and Disease Modifying Capacity” for further details). The clinical benefits may depend on the nature of the allergen extracts.

Assessing the Response to Allergen Immunotherapy

The assessment of the response to AIT is made clinically by the improvement of symptoms and reduction for the need of medications (symptom score, medication score, or combined symptom medication scores [CSMSs]) and assessment of QoL. Tests such as quantitative SPT, bronchial hyperresponsiveness test, and immunological parameters may also be used. However, these parameters may not always correlate with improvement in allergic disease status of patients. Measurement of total IgE has no value for such assessment.^[2],[3]

Nonquantitative skin testing (demonstrating skin test reactivity to a single dilution) or serum-sIgE antibody testing of patients during AIT is not recommended because it has not been demonstrated that they correlate with a patient's clinical response. Efficacy and clinical contraindications should be assessed regularly.^[2],[3] Studies have shown that AIT inhibits allergen-driven TH2 response, so the cytokines typical for TH1 versus TH2 responses could be used as markers to judge the response of AIT. The immunological markers such as Treg cells with increase in IL-10 and IgG4 blocking antibody) correlate well with reduction in immediate skin test response and decrease in late phase response, which may be used to assess the response and to decide when to stop AIT.^[94]

Efficacy: Immunotherapy Trials Including Cochrane Database Analysis

Subcutaneous immunotherapy

SCIT is effective in the treatment of allergic rhinitis, allergic conjunctivitis, and allergic asthma, in both children and adults. It is also used in the treatment of venom hypersensitivity, which is discussed separately. The parameters that indicate clinical efficacy of a treatment are reduction in symptoms and/or drug intake of a magnitude that significantly reduces morbidity.^[95] The clinical efficacy of SCIT has been validated in numerous clinical trials in children and adults. Clinical efficacy has been confirmed for allergen products from birch, grasses, mountain cedar, cypress, olive, Parietaria, ragweed, cat, D. pteronyssinus, Alternaria, and Cladosporium.

Fundamental questions on AIT are (1) whether it has potential to provide long-term benefit following its discontinuation and (2) whether it can prevent either disease progression or the onset of new allergic sensitivities.^[96] Without long-term reduction in disease severity and disease-modifying capability, AIT may not be cost-effective and consequently not be a real alternative to pharmacologic treatment.^[97] Previous studies on IT indicate that the treatment may have a long-lasting effect. A controlled study by Durham et al.^[92] has documented the long-term efficacy of AIT after withdrawal of the treatment, following a double-blind, placebo-controlled trial.^[98]

As per the WHO ^[99] and AAAAI recommendations,^[3] at present, allergen avoidance and IT are the only treatments that modify the course of an allergic disease either by preventing the development of new sensitivity or by altering the natural history of disease or disease progression. The optimal dose for SCIT has been recommended as the maintenance target dose for all patients. Doses of 5–20 micrograms of the major allergen are optimal doses for domestic mites, cat dander, ragweed pollen, and hymenoptera venoms. These doses are tolerated by the majority of patients with allergic diseases without difficulty.

Allergic rhinitis

AIT alters allergic disease through a series of injections of clinically relevant allergens and has been recognized as the only therapeutic option known to alter the natural history of allergic rhinitis.^[100],[101] According to the AAAAI,^[102] AIT is successful in patients with seasonal allergic rhinitis and in patients suffering with perennial allergic rhinitis. Hence, subcutaneous AIT was approved for the management of allergic rhinitis and/or allergic asthma. However, AIT is currently indicated as a supplement to allergen avoidance and to pharmacotherapy.^[103] Its efficacy in the prevention of allergic march and the development of asthma among patients with allergic rhinitis has been demonstrated.^[104],[105] Data were extracted from 16 studies showing clinical effectiveness of SCIT in the treatment of allergic rhinitis, involving 759 patients (546 adults, 53 children, 160 all ages). In 15 (94%) of the studies, SCIT led to significant improvement in both symptoms and medication scores.^[94] Its efficacy has been validated in many trials, using grass, ragweed, and birch pollen extracts.^[96] Importantly, SCIT has been shown to be effective even in patients with severe seasonal rhinitis that is resistant to conventional drug therapy. There was a highly significant decrease versus median placebo (95% confidence interval [CI] for difference between medians) in total symptom scores (P = 0.001), total drug use (P = 0.002), and visual analog symptom scores (P = 0.02), 2.2 versus 5.5 (−4.8–−0.5). Provocation tests after allergen IT showed a greater than 10-fold reduction in immediate conjunctival allergen sensitivity (P = 0.001), a 40% decrease in early phase response (P = 0.02), and a 57% decrease in the late phase (P = 0.001) cutaneous response after intradermal allergen challenge.^[98]

A Cochrane review, on the meta-analysis of 51 randomized double-blind placebo controlled trials involving 2871 subjects with seasonal allergic rhinitis or controls, has shown that AIT results in significant improvement in overall symptoms, medication use, and QoL. Symptom score data from 15 trials were suitable for meta-analysis and showed an overall reduction in the AIT group (standardized mean difference [SMD] −0.73 [95% CI − 0.97–−0.50, P< 0.00001]). Medication score data from 13 trials showed an overall reduction in the AIT group (SMD of − 0.57 [95% CI − 0.82–−0.33, P< 0.00001]). Adrenaline was given in 0.13% (19 of 14,085 injections) of those on active treatment and in 0.01% (1 of 8278 injections) of the placebo group for treatment of adverse events. There were no fatalities.^[106],[107]

A current meta-analysis (2013) evaluated 17 clinical trials (up to April 2011) for the efficacy of SCIT in patients with seasonal allergic rhinitis.^[108] This analysis found a reduction in the symptom scores (SMD − 0.65; 95% CI − 0.85–−0.45; P< 0.00001; all 17 studies), the medication scores (SMD − 0.55; 95% CI − 0.75–−0.34; P< 0.00001; 16 studies), the CSMSs (SMD − 0.48; 95% CI − 0.67–−0.29; P< 0.00001; 8 studies) as well as an improvement in the QoL scores (SMD − 0.53; 95% CI − 0.66–−0.39; P< 0.00001; 8 studies).

The benefits of AIT for perennial rhinitis are less than for seasonal rhinitis. In part, this reflects the difficulty in determining the extent to which allergy is responsible for perennial symptoms. Nevertheless, clinical trials have shown a definite benefit in appropriately selected subjects.^[109] Clearer evidence has been obtained in perennial rhinitis due to pet allergy. Several studies have shown a marked improvement in tolerance of cat exposure after SIT, validated both on challenge tests and simulated natural exposure.^[110]

Bronchial asthma

A meta-analysis of 75 SCIT trials concluded that there is a significant reduction in asthma symptoms and drug requirement as well as in bronchial hyperreactivity with SCIT.^[111] SCIT has been found to maintain a persistent improvement after discontinuation of IT ^{[92],[105],[112],[113]} and also reduces the risk of future development of asthma in rhinitis cases.^{[92],[94],[105],[113],[112],[113],[114],[115],[116]} Successful IT prevents development of new allergen sensitivities in monosensitized individuals.^{[117],[118],[119]}

A 2003 Cochrane review included 75 trials with a total of 3506 participants (3188 with asthma) for data analysis in a meta-analysis.^[111] There were 36 trials of HDM allergy, 20 pollen allergy, 10 animal dander allergy, 2 Cladosporium mold allergy, 1 latex, and 6 for multiple allergens. Concealment of allocation was assessed as clearly adequate in only 15 of these trials. Significant heterogeneity was present in a number of comparisons. Overall, there was a significant reduction in asthma symptoms and medication and improvement in bronchial hyperreactivity following AIT. Furthermore, a significant improvement was therein asthma symptom scores (SMD − 0.72, 95% CI − 0.99–−0.33) and it would have been necessary to treat 4 (95% CI 3–5) patients with SCIT to avoid one deterioration in increased medication. AIT significantly reduced allergen-specific bronchial hyperreactivity, with some reduction in nonspecific bronchial hyperreactivity as well. However, there was no consistent effect on lung function.

The 2010 updated Cochrane meta-analysis “Injection allergen IT for asthma” included 88 trials (13 new trials).^[120] There were 42 trials of IT for house mite allergy; 27 pollen allergy trials; 10 animal dander allergy trials; two Cladosporium mold allergy, 2 latex, and 6 trials looking at multiple allergens. Overall, there was a significant reduction in asthma symptoms and medication and improvement in bronchial hyperreactivity following AIT. There was a significant improvement in asthma symptom scores (SMD − 0.59, 95% CI − 0.83–−0.35 [P < 0.00001]) and it would have been necessary to treat three patients (95% CI 3–5) with IT to avoid one deterioration in asthma symptoms. Overall, it would have been necessary to treat four patients (95% CI 3–6) with IT to avoid one requiring increased medication. AIT significantly reduced allergen-specific bronchial hyperreactivity, with some reduction in nonspecific bronchial hyperreactivity as well. There was no consistent effect on lung function. If 16 patients were treated with IT, one would be expected to develop a local adverse reaction. If nine patients were treated with IT, one would be expected to develop a SR (of any severity).

A recently published meta-analysis evaluated the efficacy and safety of SCIT in mite-sensitized subjects with asthma.^[121] A total of 796 subjects from 19 different randomized controlled trials (RCTs) were included in this analysis. SCIT significantly reduced the asthma symptom scores (SMD − 0.94, 95% CI − 1.58–−0.29, P = 0.004) and the asthma medication scores (SMD − 1.06, 95% CI − 1.70–−0.42, P = 0.001) compared with the control group. One study conducted solely in children with allergic asthma, in which SCIT was employed using an hypoallergenic extract of HDM, showed improved asthma control as well as significant reduction in the required doses of inhaled corticosteroids compared with the control group not treated with SCIT.^[122]

A meta-analysis prepared by the Johns Hopkins University Evidence-based Practice Center for the Agency for Healthcare Research and Quality (AHRQ, USA) included 74 references that investigated the efficacy and safety of SCIT.^[123] In this meta-analysis, the strength of evidence was high that SCIT reduces asthma symptoms, rhinitis symptoms, conjunctivitis symptoms, asthma medication use, asthma plus rhinoconjunctivitis medication use, and rhinoconjunctivitis-specific QoL. The strength of evidence is moderate that SCIT reduces rhinoconjunctivitis medication use, relative to usual care, which includes pharmacotherapy.

Atopic dermatitis

AD may respond to SCIT if the patient is sensitized to inhalant allergens although this conclusion is based on a small number of studies ^[3] of HDM allergic patients, including one randomized trial of 51 patients.^[124],[125] Negative studies also exist.^[126] The impact of IT on AD in patients sensitized to pollens or other aeroallergens has not been studied. Thus, the use of SCIT to treat AD requires careful observation of the patient's clinical status, especially during the buildup phase of treatment. One randomized double-blind dose-range finding SCIT trial on 89 adult patients with a chronic form of AD and sensitization to HDMs revealed a significant improvement of the scoring atopic dermatitis (SCORAD) over a 1-year therapy course.^[125] In a more recently published DBPC-Phase-III study (SCIT) on 168 adult patients, a significant improvement in the SCORAD was only demonstrated in a subgroup with severe forms of AD.^[127]

Preventive and disease modifying capacity

The capacity of SCIT to prevent the development of new sensitizations has been investigated in three nonrandomized studies in monosensitized patients.^{[117],[118],[119]} In an open retrospective study, Purello-D'Ambrosio made a follow-up of 7182 monosensitized (to different allergens) patients treated with SCIT for 4 years and off IT for 3 years.^[118] The control group consisted of 1214 matched patients followed for 7 years. The development of sensitization to new allergens showed a clinically relevant and statistically significant difference at the 4-year follow-up, with figures of 68% in the control group versus24% in the IT group and at the 7-year follow-up 78% and 27%, respectively. Pajno et al. followed 75 SCIT-treated children monosensitized to HDMs and 63 comparable controls treated pharmacologically for 6 years.^[119] In the IT group, 74% continued to be monosensitized versus33% in the control group. A prospective controlled prolonged follow-up study demonstrated the ongoing clinical benefit 12 years after discontinuation of hypoallergenic AIT as compared to pharmacotherapy only. Furthermore, the reduction in onset of new sensitization (58% in the AIT group and 100% in the control group) is sustained at the 12-year follow-up. In addition, there was a tendency for lower prevalence of seasonal asthma in the post-AIT group.^[105] Although these studies are of interest, prospective randomized, controlled studies are needed.

In India, a double-blind placebo-controlled study showed significant improvement in clinicoimmunologic parameters in asthma and rhinitis patients after 1 year of IT with whole-body mosquito extract.^[128] A placebo-controlled study demonstrated early relapse of symptoms after discontinuation of treatment in patients receiving pharmacotherapy, whereas it was 3–5 years in IT group patients.^[129]

SCIT might prevent the progression of rhinitis into asthma. A multicenter pediatric study investigated the capacity of IT in children with allergic rhinitis to downregulate the development of asthma.^[130] Children allergic to birch and grass pollen and no symptoms of lower airway hyperreactivity were randomized to pharmacologic treatment. After 3 years of treatment, the number of children developing clinical asthma was statistically reduced in the IT group. The development of asthma was in 24% children in IT group versus44% in the drug-treated group, indicating high risk of developing asthmatic symptoms in allergic rhinitis children is diminished by IT. Bronchial hyperresponsiveness to methacholine decreased significantly in IT-treated children, but only 2 out of 40 children with asthma at inclusion were free of asthma after 3 years, indicating that IT has a greater capacity for preventing than for curing asthma. Further studies are needed to clearly define the preventive capacity of SCIT.

Studies on Sublingual Immunotherapy

Due to new controlled trials in adults ^{[131],[132],[133],[134],[135],[136],[137]} and children,^{[138],[139],[140]} some with high patient numbers, data on the efficacy of SLIT are also available. SLIT has been suggested to be a particularly attractive treatment for children where safety is paramount and outpatient, and home-based therapy is clearly preferable. However, more studies in children are urgently required because several issues remain unsolved: for example, optimal doses and duration of treatment in children, the evaluation of quality-of-life and compliance with administration, of vaccine at home. Besides, storage of the allergen product during the time family is out of home, for example, during holidays and dosing during acute, but prolonged gastroenteritis also required to be investigated. The excellent safety profile of SLIT and the fact that injections are not required with this approach raise the possibility that SLIT could be given to children below the age of 5 years, in an attempt to modify the natural course of the allergic disease. However, definitive trials are required to achieve this objective.^[141],[142]

Allergic rhinitis

A meta-analysis published by the Cochrane Library on the clinical efficacy of SLIT in patients with rhinitis included 22 double-blind, placebo-controlled clinical trials, and a total of 979 patients.^[143] There was significant heterogeneity for most comparisons, likely due to the use of several alternative scoring systems in different studies. However, results showed a significant reduction in rhinitis symptoms and medication requirements. Out of 22 studies, 12 included children <15 years whereas four studies were conducted exclusively in children. The doses of allergen used in different studies were analyzed by Canonica and Passalacqua ^[88] that ranged from 3–5 to 375 times the cumulative dose of SCIT. There was no clear relationship between the dose administered and clinical efficacy; hence, more dose–response studies are needed to clearly indicate the optimal therapeutic dose. A dose–response relationship has been analyzed for ragweed extract.^[144]

The 2010 Cochrane update ^[145] included for the symptom scores 23 studies in grass pollen allergic patients (SMD − 0.35; 95% CI − 0.45–−0.24; P< 0.00001), 9 studies (including 2 using birch pollen extract) in tree pollen allergic patients (SMD − 0.42; 95% CI − 0.77–−0,06; P = 0.02), and 9 studies in HDM allergic patients (SMD − 0.97; 95% CI − 1.80–−0.13; P = 0.02). For the use of SLIT in AR, the Cochrane meta-analysis found an advantage for AIT for all allergens (P < 0.00001).

A meta-analysis published earlier this year (2015) assessed the efficacy and safety of the grass pollen sublingual tablets licensed as drugs in the treatment of patients with seasonal allergic rhinoconjunctivitis to grass pollen.^[146] Data were available in 13 RCTs for the symptom score (4659 patients) and in 12 RCTs for the medication score (4558 patients). The authors found a small treatment benefit in the symptom score (SMD, −0.28; 95% CI, −0.37–−0.19; P< 0.001) and in the medication score (SMD, −0.24; 95% CI, −0.31–−0.17; P< 0.001) and concluded that considering the low magnitude of the benefit, the convenience and easy administration do not seem to be sufficient reasons for the choice of SLIT.

Allergic asthma

Compared with allergic rhinoconjunctivitis, there are only a limited number of studies on the efficacy of SLIT in patients with allergic bronchial asthma. The 2006 Cochrane Collaboration method meta-analysis data found no significance (P = 0.07) for the use of SLIT in allergic asthma.^[147] A grass tablet study showed efficacy for SLIT in bronchial asthma in a subgroup of children with seasonal allergic asthma.^[138] With regard to IT using dust mite extracts, heterogeneous results were found in clinical trials with methodological limitations.^{[148],[149],[150],[151]}

A recent study included 604 HDM allergic patients at least 14 years of age with mild to moderate asthma treated for a 1-year period with SLIT with HDM tablets. Compared with placebo, actively treated patients exhibited a significant reduction in the dose of inhaled corticosteroids required to maintain asthma control over the course of the study period.^[152]

A meta-analysis published in September 2015 evaluated a total of 454 children with asthma/rhinitis who were sensitized to HDMs and were treated with SLIT or control for between 4 months and 3 years.^[153] The analysis indicated that dust mite SLIT therapy was effective in reducing asthma symptoms and in increasing sIgG4 but did not significantly reduce medication scores or specific D. pteronyssinus IgE levels. The authors noted that the data are not enough to support the use of dust mite SLIT in children with asthma.

Preventive and disease-modifying capacity

A randomized controlled open SLIT study in children has shown preventive effect on asthma onset.^[154] In control group, 18 of 44 developed asthma versus8 of 45 in the sublingual group after 3 years of treatment. Another randomized controlled open study demonstrated the prevention of new sensitizations in a 3-year long trial ^[155] whereas this effect was not observed in another open study.^[156],[157]

The long-term effect of SLIT was investigated in an open controlled study including 60 mite-sensitive asthmatic children aged 3–17 years.^[156] Allocation to IT or pharmacotherapy group was based on parental preference. SLIT was given for 4–5 years and the children followed up for 10 years. At 10 years, there was a significant reduction in the onset of asthma, use of asthma medication, and an increase in peak expiratory flow rate as compared to control group.

Allergens to be used for SLIT are limited and no Indian clinical trial data on SLIT (i.e., randomized double-blind placebo-controlled studies) are available. The dosage of SLIT also ranges from 50-fold to 100-fold compared to the doses which are commonly given for SCIT. In addition, different manufacturers have different doses for the SLIT allergens which are not comparable.

The summary of efficacy data for allergen immunotherapy from Cochrane Reviews/meta-analysis is shown in [Figure 2].^{[120],[145],[147],[158]}

Figure 2: Summary of efficacy data for allergen immunotherapy from Cochrane reviews^{[120],[145],[147],[158]}

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Studies Comparing Sublingual and Subcutaneous Immunotherapy

Both the routes of administration, SCIT and SLIT, have shown efficacy and safety in clinical trials and meta-analyses. There are few trials and meta-analyses which have compared that there are two routes of administration.

The meta-analysis prepared by the Johns Hopkins University Evidence-based Practice Center for the AHRQ, USA, investigated the efficacy and safety of subcutaneous and SLIT.^[123] The researchers reviewed the head-to-head comparative trials of the two routes of administration [Table 8].^[123] The analyses revealed:

For allergic asthma symptom control: The studies support SCIT over SLIT (strength of evidence, low [4 studies, n = 171])
For allergic nasal and/or eye symptoms: The strength of evidence was moderate that SCIT is more effective than SLIT for reducing allergic nasal and/or eye symptoms (6 RCTs, n = 412)
The data were inadequate to comment on reduction of medication use, symptom and medication reduction, and QoL. The strength of evidence lowly favors SCIT for reducing asthma symptoms and for controling nasal and eye symptoms.

Other systematic reviews which have compared the two routes of administration (i.e., SCIT and SLIT) are detailed in [Table 9].^[159] These include the studies in adult as well as the pediatric population.

Table 9: Systematic reviews comparing subcutaneous and sublingual immunotherapy

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Systematic reviews and meta-analyses of RCTs of SCIT, SLIT, or both versus placebo (indirect and direct comparison) suggest that SCIT might provide greater clinical and immunologic efficacy. However, more studies with a greater number of patients are needed to evaluate the magnitude of the clinical efficacy and the optimal dosage. Regarding the final choice between SCIT and SLIT, the decision needs to be made individually with each patient after careful considerations of factors.

Venom Immunotherapy

The efficacy of venom IT (VIT) has been analyzed in three controlled and several prospective uncontrolled studies which employed a usual maintenance dose of 100 μg of venom.^{[160],[161],[162]} In these studies, patients were monitored with sting provocation tests during IT.^[163] In all controlled trials with vespid, honey bee, or ant venom allergy, comparing venom with either whole-body extract or placebo, a highly significant difference was observed in favor of VIT. Here, 75%–100% of venom-treated patients tolerated re-sting without any allergic symptoms, while 64%–75% of whole-body product and 58%–72% of placebo-treated patients developed systemic allergic reactions on re-sting challenge. In the prospective uncontrolled studies, only 0%–9% of vespid allergic and around 20% of bee venom allergic patients reacted to challenge with the respective insect. These studies suggest the superior efficacy for IT with vespid or ant venom compared to honey bee venom. The patients who reacted following a course of VIT had mild symptoms than those observed before the treatment. VIT is effective in 95% of patients allergic to wasp venom and about 80% of those allergic to bee venom.^[164]

The safety of VIT is related to the nature of the venom used and the protocol. More side effects were observed during IT with honey bee venom than vespid venom.^[165] In an EAACI multicenter study of 840 patients totaling 26,601 injections, 20% of patients developed mild systemic allergic reactions, corresponding to 1.9% of injections during the dose increase phase and 0.5% during the maintenance phase.^[166] Rapid dose increase, especially with high cumulative daily doses of 200–500 μg in rush protocols, may increase the risk of side effects. In patients who cannot safely discontinue β-blockers but who have a history of moderate to severe sting-induced anaphylaxis, VIT is indicated because the risk of anaphylaxis related to a venom sting is greater than the risk of an IT-related SR.^[3]

Allergen Immunotherapy Studies in India

A limited number of studies are available on AIT from our country.^{[128], 129, [167],[168],[169]} IT for 1 year in cases of asthma and/or rhinitis has demonstrated >50% improvement in clinical parameters (symptoms).^[167] A placebo-controlled study on AIT for 6–12 months with Cocos nucifera pollen extract showed significant clinical improvement (symptom-medication score), reduction in IgE, and elevation of specific IgG in posttherapeutic patients' sera than placebo.^[168] Another study evaluated the immunological changes that follow SCIT in patients suffering from bronchial allergy and/or allergic rhinitis. The inflammatory makers (IL-5 and IL-6 levels) at 0, 3, and 6 months were compared, and it was noted that with an increase in duration of treatment, the levels of these markers decrease significantly (P = 0.003).^[170]

An open comparative study of IT versus budesonide inhalation has reported almost equal improvement in asthma patients in both the groups.^[129] However, the decline in benefit was rapid in drug treatment group than AIT after cessation of treatment. Another study determined the efficacy of HDM IT over a 15-year period.^[171] The use of IT resulted in a statistically significant improvement in both global symptom scores and forced expiratory volume 1 s in patients receiving IT when compared with those in the control group who did not receive IT. This improvement was sustained for at least 10 years after cessation of IT.^[171] Another observation presented the ongoing clinical benefit for 6–9 years in 35 patients even after discontinuation of HDM (D. farinae/D. pteronyssinus) SCIT for 3 years.^[172]

A recent double-blind placebo-controlled study on AIT with mosquito extract in asthma and allergic rhinitis patients has demonstrated significant clinical improvement, supported with changes in airway reactivity and immunologic parameters (IgE, IgG1, IgG4, and IFN-γ) from the baseline and placebo.^[128] Further, AIT with two to three mix extracts from the same allergen group is effective for insect hypersensitivity.^[169] A double-blind, placebo-controlled trial of cockroach AIT was performed for 1 year in fifty patients of asthma, rhinitis, or both. AIT with cockroach extract improved clinical and immunological status of asthma and rhinitis patients.^[128] A case study has also documented the successful SCIT with horse dander allergy in a patient with recurrent episodes of anaphylaxis on coming in contact with horse.^[173] An open-label study evaluated the efficacy of swallow SLIT and rush SCIT (25 patients in each group, with allergic rhinitis, asthma, or both) using randomization technique and followed up for 1 year.^[174] There was significant improvement in QoL in both SLIT and rush SCIT groups from baseline to end of 1 year. Another study evaluated the response to AIT in eighty patients with allergic conjunctivitis. Sixty-two percent of these showed beneficial response as documented by the symptoms and medications scores.^[175] In India, a preliminary observation has documented the steroid-sparing effect of cluster IT combined with anti-IgE, the combination being also associated with good tolerability.^[176]

A retrospective analysis of a prospective symptom review in patients receiving AIT has been conducted in India to determine the type of allergens, number of allergens, and concentration of the allergens or the combination on the efficacy of AIT. Patients received AIT with a mixture of 5–8 allergens and HDM was administered separately. The authors found that only 42% of their patients improved while 58% had no improvement or had worsening of their symptoms. It was observed that 58% of the patients, who did not benefit from AIT, received the incorrect combination of allergens. The compatibility of allergens was based on the protease activity of the individual allergens. High protease-containing enzymes included dust mites, fungal, and insect allergens. These results clearly lay emphasis on the nature of allergens and their combination used for IT. Furthermore, the inclusion of all allergens to which IgE antibodies are present, without establishing the possible clinical relevance of these allergens, dilutes the content of other allergens in the vaccine and can make AIT less effective.^[177] A double-blind placebo-controlled study evaluated the efficacy of single insect extract (cockroach, housefly, or mosquito) and mix allergen IT (two or three insect extracts) with placebo. In this study of insect AIT, mixed and/or single insect AIT for 1 year demonstrated significant improvement in clinical (skin reactivity, airway reactivity, and symptom score) and immunological (IgE/IgG4 and IgG1/IgG4 ratio) parameters.^[169]

Another study – a double-blind, placebo-controlled trial of cockroach AIT performed for 1 year in fifty patients of asthma, rhinitis, or both – evaluated the efficacy of AIT by change in skin reactivity and clinical parameters such as symptom/drug score, airway reactivity, and immunological parameters. AIT with cockroach extract demonstrated significant improvement in clinical parameters of active group patients compared with baseline values and placebo group. sIgE levels showed a modest reduction, while IgG4 levels increased significantly in active AIT group after 1 year. IgE immunoblotting demonstrated reduction in intensity and number of specific bands, whereas IgG4 binding showed more number and distinct bands following AIT. Active group patients showed correlation between increase in IgG4/IgG1 ratio and reduction in symptom score post-AIT.^[178]

A prospective nonrandomized with 6-year follow-up study evaluated the safety of SLIT in pregnancy in Indian patients. One hundred and fifty-five patients received SLIT with either HDM (D. farinae) or a mixture of up to five allergens during 185 pregnancies.^[179] Two control groups did not receive IT; Group A (85 patients) received budesonide 400 μg twice daily and Group B (40 patients) received rescue salbutamol inhalation. In this study, there were no episodes of SRs, but there were 11 episodes of LRs (oral) to SLIT, consisting of mild itching in the oral cavity and/or swelling of lips. Patients, in whom LRs were noted, delivered normally. The incidence of abortion in the salbutamol group was higher than in the general population (P < 0.05) and was higher in both control groups when compared with the SLIT group (P < 0.05). The incidence of perinatal deaths, prematurity, and toxemia of pregnancy was also higher in both control groups as compared to the SLIT group, but within the expected incidence for the general population. Another study, which retrospectively analyzed the safety of SCIT in pregnancy, also concluded that that IT for allergic diseases is safe in pregnancy.^[180]

All these studies show substantial evidence in favor of allergen IT; however, more studies are required involving long-term clinical trials from the country.

Safety of Allergen Immunotherapy –

A Global Perspective

The administration of allergens into an IgE-sensitized individual always implies a risk, however small, of inducing local and systemic side effects.^{[3],[99],[169]} LRs are fairly common with both SCIT (erythema, pruritus, and swelling at the injection site) and SLIT (oropharyngeal pruritus, swelling, or both), affecting up to 82% of patients receiving SCIT ^[3] and 75% of patients receiving SLIT.^[181] Gastrointestinal symptoms associated with SLIT can be classified as LRs (if only associated with oral mucosal symptoms) or SRs (if occurring with other systemic symptoms). LRs were “deemed not bothersome at all or only slightly bothersome” by 82% of SCIT survey respondents, with only 4% indicating that they would stop SCIT because of the LR.^[182] LRs are not predictive of subsequent SRs with either AIT route.^[183],[184] No study found that increased frequency of large SCIT LRs increases the risk for future SRs.^[185]

Evidence suggests that the patients most likely to develop anaphylaxis are those who are highly sensitive as determined by skin tests or sIgE tests, patients with more severe disease (in particular with chronic and uncontrolled asthma)^[186] and prior SCIT-related SRs among others [Table 10].^[187] It must be noticed that the occurrence of adverse events with SCIT largely depends on the allergen type and preparation. Higher frequency is seen with native allergens compared to the hypoallergenic preparations and in animal dander compared to pollen and mite.^[2] Systemic side effects occur more frequently in patients during the induction (up-dosing) phase of treatment compared to maintenance therapy.^[188],[189] SCIT-related SRs can range in severity from mild to life-threatening or fatal anaphylaxis. The incidence of SCIT SRs varies depending on the induction schedule, augmenting factors, premedication, and the degree of sensitization. In most surveys, the rate of SRs with nonaccelerated SCIT induction is approximately 0.1%–0.2% of injections and 2%–5% of patients.^[190],[191]

Table 10: Risk factors for systemic reactions during allergen immunotherapy

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Compared with SCIT, the SLIT-related SR rate is significantly lower, and severe SRs are relatively uncommon. When introducing a new route of administration, safety is a priority, especially when treatment is self-administered at home.^[95] Clinical trials and pharmacosurveillance studies have demonstrated a very low rate of systemic adverse effects and no life-threatening systemic side effects with SLIT.^[192],[193] In a comprehensive review of 104 SLIT studies published through October 2005, the SLIT-related SR rate was 0.056% of doses administered (i.e. 14 probable SLIT-related serious adverse events, which translated to 1.4 serious adverse events per 100,000 SLIT administered doses).^[181] The Food and Drug Administration (FDA)-approved product information of the three SLIT tablets includes a warning about the possibility of severe allergic reactions from SLIT and a recommendation that an epinephrine autoinjector be prescribed to patients receiving allergy tablets in the event a severe allergic reaction should occur. To date, there have been no confirmed reports of SLIT-related fatalities, but SRs of a severity to be categorized as anaphylaxis have been reported.^[194] Unlike SCIT, the incidence of SRs does not appear to be related to induction schedule, allergen dose, symptomatic asthma, or degree of sensitization. Because SLIT is administered in a setting without direct medical supervision, specific patient instructions should be provided regarding management of adverse reactions and the clinical scenarios when the administration of SLIT should be postponed (e.g., asthma exacerbation, acute gastroenteritis, and stomatitis or esophagitis).

SRs (anaphylaxis) are generally rare, but facilities for its management should be available at the place of skin testing and IT. SRs are categorized into immediate SRs (occurring within 30 min) and late SRs (debut >30 min after injection)
Important symptoms of anaphylaxis include change in voice, frequent change in posture, itching in eye and skin, redness in eye, appearance of symptoms – such as rhinitis, asthma, and urticaria, fall in blood pressure and feeble pulse, mental confusion, sinking sensation, and losing consciousness
Early signs of a severe reaction include a burning sensation and pruritus of the palms and soles; perianal or perigenital pruritus; an urge to defecate and urinate; sneezing attacks and generalized pruritus. In addition, further respiratory and/or cardiovascular symptoms may occur rapidly
Sequential increase in the size of swelling at the site of injection is suggestive of impending anaphylaxis
Other complications may include vasovagal attack.

WAO SCIT SR grading system should be utilized to identify SRs and grade them accordingly.^[190]

Anaphylaxis and its management

SRs (anaphylaxis) may occur in patients while skin testing with some antigens or initiation phase). Anaphylaxis refers to severe allergic reaction, in which prominent dermal and systemic signs including symptoms manifest. The full-blown syndrome includes urticaria (hives) and/or angioedema with hypotension and bronchospasm. The classic form, described in 1902, involved prior sensitization to an allergen with later re-exposure, producing symptoms through an immunologic mechanism. An anaphylactoid reaction produces a very similar clinical syndrome but is not immune-mediated.

Pathophysiology of anaphylaxis is characterized by rapid onset of increased secretion from mucous membrane, increased bronchial smooth muscle tone, decreased vascular smooth muscle tone, and increased capillary permeability after exposure to an inciting substance. These effects are produced by the release of mediators, such as histamine, leukotriene C4, prostaglandin D2, and tryptase. The release of these mediators are immune mediated involving type I allergic reaction that occurs when the antigen (allergen) binds to antigen-sIgE attached to previously sensitized basophils and mast cells. The mediators are released almost immediately when the antigen binds.

The most common inciting agents in anaphylaxis are parenteral antibiotics (especially penicillins), intravenous contrast materials, hymenoptera stings, and certain foods (most notably, peanuts). Oral medications and many other types of exposures also have been implicated in anaphylaxis. Anaphylaxis may sometimes be idiopathic.

Anaphylactic reaction is clinically manifested by respiratory distress, laryngeal edema, and/or intense bronchospasm, often followed by vascular collapse or by shock without antecedent respiratory difficulty. Cutaneous manifestations exemplified by pruritus and urticaria with or without angioedema are characteristic of such systemic anaphylactic reactions. Gastrointestinal manifestations include nausea, vomiting, crampy abdominal pain, and diarrhea.

Adrenaline/epinephrine is the drug of choice for the management of anaphylaxis.

Prehospital interventions include high-flow oxygen, cardiac monitoring, and facility for intravenous line. Active airway intervention is needed in rare cases but may be difficult due to laryngeal or oropharyngeal edema. Inhaled beta-agonists are used to counteract bronchospasm and should be administered to patients having wheezing. For large-volume intravenous fluid resuscitation, isotonic crystalloid solutions (i.e., normal saline, ringer lactate) are preferred. With mild cutaneous reactions, an antihistamine alone may be sufficient. In patients with systemic manifestations of anaphylaxis, epinephrine is to be administered. Patients taking β-blockers may be resistant to the effects of epinephrine. Glucagon may be effective in this situation. Administration of corticosteroids is used in anaphylaxis primarily to decrease the incidence and severity of delayed or biphasic reactions. Corticosteroids may not influence the acute course of the disease; therefore, they have a lower priority than epinephrine and antihistamines.

Essential equipment/drugs (emergency kit) for the treatment and monitoring of systemic anaphylactic reactions ^[81] should be available, while skin testing and injection (s) for AIT, as follows:

Stethoscope, blood pressure monitor
Adrenaline (1 mg/ml) for injection
Antihistamine, corticosteroids, and vasopressor for injection or oral treatment
Bronchodilator (rapidly acting β2 agonist for inhalation or intravenous injection)
Syringes, needles, tourniquet, and equipment for infusion
Saline for infusion
Oxygen (with face mask/nasal cannula) and suction equipment
Silicone mask and equipment for manual ventilation
Forms for recording the course and treatment of anaphylaxis.

Precautions for systemic side effects

Before deciding the dose of allergen, a careful evaluation of the patient suitability to receive the scheduled dose is required to avoid systemic side effects. The precautions recommended are as follows:^[81],[195] (1) IT should not be started during peak allergen season and (2) injections should not be administered when the patient has clinical symptoms or the symptoms should be controlled by adequate medication.^[92] As a safety precaution, a reduction in allergen dose during allergen season is commonly recommended.

AIT injections (SCIT) in patients with airway infection or other significant diseases within the last 3 days can be postponed
Injections (SCIT) in patients with deterioration of allergy symptoms or increased need for anti-allergic drugs due to recent allergen exposure within the last 3 days should be postponed
Injections (SCIT) should be postponed in patients with decreased lung function <80% of personal best value. In asthmatic patients, measuring lung function before each injection is mandatory (peak flow measurement is sufficient)
The scheduled dose of antigen can be reduced if the interval between injections has been exceeded. The magnitude of reduction depends on the degree exceeded and should be defined in the clinical guidelines
The scheduled allergen dose should be reduced in case of an SR at the preceding visit. The magnitude of reduction depends on the severity of the reaction and should be defined in the clinical guidelines. In case of anaphylactic and other life-threatening reactions, the continuation of SCIT should be carefully evaluated (except in case of hymenoptera venom allergy, in which it actually reinforces the indication for IT)
Allergen injections (vaccine) should be administered separately from other vaccination for infectious diseases by at least a gap of 1 week
Conventionally, the late LR at the injection site is used to adjust the allergen dosage for the next allergen administration. However, studies have indicated that the late LR at the preceding injection is not related to a risk of developing an SR at the next injection ^[195]
Preinjection monitoring of patients also includes a check of any drug intake that may either increase the risk of systemic side effects or render the treatment of anaphylactic reactions more difficult. Here, the β-blockers are the most important example.^[196] Heavy drinking of beer may similarly increase risk due to inhibition of the histamine-converting enzyme diamine oxidase ^[197]
Antihistamine pretreatment during the initial phase of AIT has shown to reduce the frequency and severity of systemic side effects.^[198] In a controlled trial of hymenoptera VIT involving a small number of patients, antihistamine pretreatment was associated with a better clinical efficacy.^[199] However, further studies are required on this aspect. A potential problem is that the use of antihistamine pretreatment may mask a mild reaction, which would otherwise help in dose modification.

Special Considerations

Monoallergen immunotherapy and mix allergen immunotherapy

One important variable in the administration of SCIT is the use of a single or multiple allergens. For example, allergy/immunology specialists in the United States generally administer mixtures of all of the major allergens (or a representative of each group of allergens) to which the patient has been shown to be sensitive. In contrast, it is common in Europe to administer only the one or two allergens that appear to cause the most symptoms for that individual patient. Most of the studies in India have also been on multiple allergen AIT. However, globally, most of the studies of SCIT efficacy used a single allergen, and thus, the efficacy of multiple allergen SCIT has not been extensively evaluated in clinical studies.^[187]

The prevalence of polysensitization has been documented to increase with age, and a majority of the patients consulting an allergist are polysensitized. A polysensitized patient does not necessarily have polyallergy [Box 3 for their definitions].^[200]

If two or more allergens are recognized as clinically significant, then AIT may be initiated with parallel 2-AIT (i.e., both allergens as individual AIT) or mixed 2-AIT. The European Medicines Agency has recommended that allergists should mix nonrelated allergens as little as possible and should not mix seasonal and perennial allergens or allergens with proteolytic activity (such as extracts of HDMs, molds and insects) without justification. Mixing allergens clearly has an impact on pharmaceutical parameters (stability and dosing) and clinical effects (optimal dose and safety). The authors of the review article also recommend that AIT with three or more allergen sources should only be considered in the very rare cases, in which all the allergens clearly cause severe symptoms.^[200]

Understanding the principles of homologous groups as suggested by Lorenz et al. can guide the clinician on the physicochemical and biological characteristics of allergen extracts that can help in defining the strategy of monoallergen IT or mixing of allergens.^[201] Homologous groups have been suggested only for the mites (Dermatophagoides species) and the pollen allergens. D. pteronyssinus and D. farinae belong to the homologous groups of HDMs. Among tree pollens, three groups have been described – the birch group or Fagales group, group of Oleaceae, and group of Cupressaceae. In grasses/cereals, sweet grasses of the Poaceae (Gramineae) family, subfamily of Pooideae have been identified as a homologous group. A group of weed pollen has also been described. Homologous groups have not been defined for insect venoms, animal dander, and molds/fungi.

Within a homologous group (such as Dermatophagoides species), the use of a single course of AIT with a mixture of allergens that mimic natural exposure is recommended. Use of separate AIT formulations is preferable when treating with two nonhomologous allergens.

When mixing two allergens from the homologous group, the ratios between the individual allergen sources should be the same.

Skin test and allergen immunotherapy during pregnancy

Do not perform skin testing in a pregnant woman
Do not start IT in a pregnant woman
Skin testing and IT are to be avoided up to 6 months after delivery or earlier if lactation is discontinued before
Do not discontinue IT if person is already on IT started much before pregnancy and receiving benefit from the therapy.

Allergen immunotherapy in children

Compliance with the injection regimen may be affected by age and may be problematic, particularly during the adolescent years. Children should accompany a parent, guardian, or other responsible person with them at each visit. It is recommended to start IT at an early age in allergic children to modify the natural course of allergic disease.

Airway remodeling may start early in life, especially in children with severe asthma,^[202] and ongoing airway inflammation and remodeling in adolescents and young adults may increase the risk of asthma later in life.^[203] As documented earlier, there is evidence that early-specific injection IT reduces the risk of asthma in children with allergic rhinoconjunctivitis ^[130] and diminishes the risk of new sensitizations in monosensitized children.^[118],[119]

Age limit for AIT in children:^[8]

Age <2 years is an absolute contraindication for AIT
Age 2–5 years is a relative contraindication for AIT
Age ≥5 years can be prescribed AIT.

Quality Control of Allergen Extracts

Several allergen vaccines (extracts) are available commercially in the country. It is recommended that allergen manufacturers should supply vaccines tested for consistency relative to an in-house reference standard. There has been significant progress in allergen standardization in recent years, and a large number of standardized allergen extracts are marketed in the US and European countries. Indian researchers have also published their work on biological standardization of pollen such as R. communis and Hydrangea integrifolia.^[204]

In recent years, a lot of knowledge has been generated in India on characterization of major/minor allergen of pollen, fungi, food, and insect sources.^{[34], 51, [205],[206],[207],[208],[209],[210]} However, the purified proteins (major allergens) and monoclonal/polyclonal antibodies are not available for characterization based on major allergen content. Under these circumstances, allergen extracts are standardized based on weight/volume and protein estimation by modified Lowry's, bicinchoninic acid assay, or micro Kjeldahl method.^[211] Researches have shown that allergen source material processed by freeze drying gives better quality extracts.^{[207],[208],[209]} The pollen contents in the samples/raw materials should be >90% for grasses/weeds and >95% in case of trees.

Most of the allergenic proteins (>80%) come in the solution within first few minutes of extraction. Recent studies have shown that 4–8 h extraction in PBS (pH 7.4) or ammonium bicarbonate (pH 8.0) yields extracts with optimum allergenic potency.^{[51],[208],[209]} The extraction buffer should contain phenyl methyl sulfonyl fluoride and EDTA as protease inhibitors.

Fifty percent glycerol is a good stabilizer of proteins in SPT solutions. However, same concentration cannot be used for therapeutic extracts and the lower concentrations are not effective.^[212] Recently, sucrose or epsilon-amino caproic acid (EACA) has been used successfully for stabilizing grass pollen and cockroach extracts.^[209],[212] Cool gel packs or cold chain should be used/developed for transporting the extracts throughout the country.

Allergen extract(s) vary from one manufacturer to another; hence, it is suggested that diagnostic and therapeutic allergen extracts should be procured from the same allergen manufacturer.

Drug controller of India/state unit(s) regulates the allergen manufacture in the country. Currently, the emphasis is on good manufacture practice to be implemented in these drug antigen units. However, the coordinated efforts of experts from ICAAI, Antigen Units and Drug Regulatory Authorities, are required to upgrade the quality control of allergen extracts following standard WHO/IUIS/EMA protocols. In fact, there is need to develop allergen certification centers in the country such as FDA and Centre for Biologics Evaluation and Research in the USA and Paul Ehrlich Institute in Europe.

The methods for antigen preparation and quality control of extracts/vaccine are summarized below for reference:

Allergy units (AUs) recommended for defining potency of extracts vary across different countries. Hence, at present, weight/volume, protein estimation (PNU in μg/ml), and SDS-PAGE protein profile should be followed for maintaining the quality of antigen in different batches
Source material for antigen extraction should be freeze dried, fungal culture (extracts) of 10–20 days should be taken, and PBS of 0.1 M, pH 7.2 has been found most suitable for antigen extraction
For stability of aqueous extracts, addition of sucrose or EACA is recommended
Allergen extracts should be free of contaminants including of aflatoxins and endotoxins
Sterility test is required for each batch of antigen extracts
Storage of antigen:

The allergen extracts/vaccines should be stored at 2°C–8°C in a refrigerator
In case of withdrawal of more antigen from the vaccine vial, it should not be injected back in vial to avoid contamination
In case of electricity failure for more than 2 h, keep vaccine in an ice box or any other cooling device/pack
Transportation of antigen should be done using a cooling container.

Standard Prescription (Protocol) for Perennial Subcutaneous Immunotherapy

The allergens for AIT are decided after correlating with history, evidence of exposure to the allergen in the patient environment, precipitation of symptoms after exposure, and skin test positivity preferably with an SPT
In cases of rhinitis and sinusitis, it is important to exclude mechanical causes such as gross DNS
Before initiating AIT, patients must be informed about the following: The practical procedure, type, and duration of treatment; expected effects; as well as possible risks of and alternatives to treatment
Most of the published randomized controlled studies of both SCIT and SLIT are conducted with single allergen extracts. These studies dominate the meta-analyses that indicate both SCIT and SLIT are effective treatments for AR and allergic asthma. There is conflicting evidence for the effectiveness of allergen mixes.^[213] The preparation of AIT with an increasing number of extracts creates a potential for interactive effects (cross-reactivity, protease activity) that can change their allergenic and immunogenic properties. Of particular importance is the contribution of proteolytic enzymes in some fungal and whole-body insect allergenic extracts. For these reasons, the number of allergens in an AIT prescription should be limited to as low as possible, never more than 4
Recent evidence demonstrates that within a homologous group (such as Dermatophagoides species), the use of a single course of AIT with a mixture of allergens that mimic natural exposure is recommended. When mixing two allergens from the homologous group, the ratios between the individual allergen sources should be the same (e.g., one should always use 1/2 of allergen source 1 and 1/2 of allergen source 2 in a two-allergen mixture, etc.).^[200]

However, in India, the pollen from different categories may be mixed to reduce the number of injections and to improve compliance. In such cases, the amount of individual antigen should be decided depending on their skin test positivity. The greater the positivity, more is the amount of that antigen to be included in vaccine. These allergens shall be mixed in proportion of skin sensitivity.^[214] Such mixture of extracts may be diluted 10 times or more to reduce the chances of an adverse event.

Several factors need to be considered when mixing allergens, including (1) cross-reactivity, (2) optimal dose for each allergen, and (3) potential interaction between different types of allergens (e.g., proteolytic enzymes).

Allergens of the same group show cross-reactivity; hence, the most potent and relevant allergen should be selected from the group. If the relevance of the allergens are equivalent, then mixing of allergens may be utilized
Allergens to be mixed in AIT should be done with precaution as certain allergens have proteolytic enzymes and thus reduce the potency of other allergens. Hence, it is recommended not to mix HDM or fungal or insect allergens with any other allergens and prescribe these preferably in separate vials. In India, practice of mixing all the allergens in single vials is done from last more than 50 years to improve compliance and acceptability. The chances of misuse or overdose due to separate vials is a more likely particularly for less illiterate patients
AIT should be prescribed only by the physician trained in allergy and AIT and administered in his/her presence in a place having facility of managing anaphylaxis
AIT is started usually with 1:5000 w/v diluted antigen, and the injections are given two times a week starting from 0.1 ml and increased in every injection by 0.1 ml.

Use a tuberculin syringe with 26 number needle
The injections are given subcutaneously
If the dose is more than 0.5 mL – divide the injection in two sites
The allergen vial should be kept in a refrigerator between 2°C and 8°C
The schedule is as follows [Table 11] [detailed dosing schedule is given in Appendix 1].

The dosing regimen may be modified and patient can be initiated with a higher dilution in patients with higher positivity on the SPT.

Table 11: Standard dosing regimen for subcutaneous immunotherapy

Click here to view

In cases showing high skin sensitivity or AIT with single antigen showing LR/SR at initiation of AIT, higher dilution, i.e., 1:50,000 w/v, can be selected and the first injection should be given in the hospital/clinic
Usually, the maintenance dose is between 0.5 and 1.0 ml of 1:50 dilution in different patients
The duration is usually 3–5 years, but in India, where it is not possible to avoid the presence of antigens (mostly pollens, dust mites, and insects), the decision has to be individualized
AIT may be postponed if the patient is symptomatic and presents with decreased lung function (i.e., <80% of the personal best value)
Response to AIT starts slowly; however, clinical and physiological improvement has been demonstrated very shortly after the patient reaches a maintenance dose.^[3] However, the time duration and efficacy are variable among individuals
If there is no clinical improvement observed after 1 year of therapy, the possible reasons for lack of efficacy with IT should be evaluated. The following reasons may be evaluated when there is no clinical improvement: (1) Failure to remove the causative allergen exposure (e.g. animal dander), (2) exposure to high levels of allergen, (3) continued exposure to nonallergen triggers (e.g., tobacco smoke), (4) incomplete identification and treatment of clinically relevant allergens, or (5) failure to treat with adequate doses of each allergen.

If none of the above reasons are found, discontinuation of IT should be considered and other treatment options should be pursued.^[3]

In case of default – up to 1 month – no change in schedule; 1–2 months – continue with last lower dose; 2–4 months – continue with last dilution, and >4 months – restart AIT. This schedule has been advised as per the current Indian practice followed for over 50 years
Antigen for skin testing and for AIT should be procured from the same manufacturer, to avoid difference in potency of the allergen. The difference in potency of extracts among different manufacturers has been reported world over. Standardized extracts should be used whenever available. Studies evaluating major allergens have documented their presence in standardized allergens extracts
The allergen extracts produced for AIT can differ in composition and allergen activity in two AIT products.^[5] Thus, data from one AIT product cannot be extrapolated to other products even if they contain the same allergen sources.

Future of Allergy Diagnosis and Allergen Immunotherapy

Over the last 20 years, a large number of new diagnostic and therapeutic concepts have emerged in the field of allergy management.

Future of allergy diagnosis

In in vivo tests, one of the important future implications of allergy diagnosis includes availability and use of standardized allergen extracts which can improve the utility of allergy diagnosis. Preliminary studies have also evaluated the in vivo component-resolved diagnosis and have shown a promising approach.^[215] Recombinant allergens have also been used for SPT,^[216] and skin tests with recombinant and natural allergens have a similar value if the recombinant allergens have been well selected and represent all or most epitopes of the natural allergen.^[216],[217]

Provocation tests including nasal and conjunctival have been evaluated and recommended by International organizations for the definitive diagnosis of IgE sensitization and allergies. Specific NPT consists of controlled exposure to allergens and thereby eliciting a response from the nasal mucosa in an allergic individual. It is indicated for the diagnostic confirmation of allergic rhinitis and when discrepancies arise between medical history and the results of skin tests and/or serological tests. It is also used to evaluate sensitivity to the allergen, the efficacy and safety profile of treatment, and in research on the pathophysiological mechanisms of nasal response to allergens.^[218] Similarly, the conjunctival allergen provocation test reproduces the events occurring by instilling an allergen on the ocular surface. It is indicated especially when the relevance of the allergen is not obvious or in polysensitized patients suffering from IgE-mediated ocular allergy.^[219]

Another area of interest is the development of molecular allergology for the diagnosis of allergic sensitizations. Development and progress made in the field of recombinant allergens have allowed for the development of a new concept in allergy diagnosis, molecular diagnosis, or component-resolved diagnosis, which makes it possible to identify potential disease-eliciting molecules. This also presents as a new challenge for healthcare professionals for appropriate interpretation of test results; clinicians must know about the basics of allergen components, their clinical implications and must always keep in mind that sensitization does not necessarily imply a clinical allergy.^[220],[221]

The basophil-activation test (BAT) measures basophil response to allergen cross-linking IgE. The clinical impact of BAT is due to the unique ability of these cells to degranulate on cross-linking of the sIgE bound on membrane-bound high-affinity IgE receptor (FcεRI) by allergen exposure. Compared with the determination of sIgE in serum, BAT reflects a functional response as basophil activation can be induced by cross-linking of FcεRI, which requires more than binding of sIgE to allergen. The clinical applications of BAT range from diagnosis to monitoring the progress of AIT. It a multifaceted and promising tool which needs to be further well established and evaluated in clinical practice.^[222]

Future of allergen immunotherapy

Although AIT is specific, it is associated with some side effects thereby newer treatments are under research to improve IT. The future developments in AIT would include newer routes of administration including intralymphatic IT (ILIT), epicutaneous (EPIT), and intradermal AIT. In ILIT, allergen is given directly in the lymph node with the aim for higher allergen amounts in secondary organs. ILIT requires much lower doses of allergen and fewer injections than the conventional SCIT modality, while maintaining the same efficacy. EPIT has been tested with good results for both aeroallergens and food allergens. This route currently seems particularly suitable in children ^[78] and has a potential for self-administration, safe, and needle free. The epicutaneous tissue has a number of antigen presenting cells and is nonvascularized.

In addition to the newer routes, newer formulations (nanoparticles) are at early experimental stage, with positive results in animal models. Addition of adjuvants to allergen extracts is an additional possibility; crude allergen extracts can be improved by adding adjuvants, which provide an additional enhancement of the TH1 response. An organic adjuvant usually stimulates the Toll-like receptors of the innate immunity, which in turn favor the TH1-oriented response.^[223] Bacterial adjuvants are commercially available for SCIT globally and have lower number of injections. DNA adjuvants are under experimental investigation, with a single human trial.^[78]

Peptide-based IT is another future prospect. It is possible to give only allergenic fragments, instead of the whole allergenic proteins, because antigen-presenting cells recognize linear sequences. Encouraging results from clinical trial have been observed.^[78],[224] The recombinant allergens have been used to improve the IT by identifying disease-causing molecules. They have also been evaluated recently in clinical studies. However, their overall efficacy has been similar to those provided by the crude extracts.^[78] Further, pretreatment with anti-IgE before AIT may reduce the systemic allergic reactions in patients unable to reach the targeted maintenance dose for IT.

The future of AIT would also incorporate newer and upcoming indications - food allergy, being the predominant one. A Cochrane review of egg allergy reviewed four RCTs with a total of 167 recruited individuals (oral IT [OIT] 100; control 67 participants), all of whom were children (aged 4–15 years).^[225] The evidence suggested that OIT can desensitize a large number of egg allergic patients although it remains unknown whether long-term tolerance develops. In addition, there are no standardized protocols for OIT and the “data” remains experimental. Other important food allergens for which research is still ongoing include peanut and cow's milk.^[226]

Position Statements

AIT should be practiced only by allergy-trained doctors (physicians [MD], pediatricians, ENT surgeon, pulmonologists, dermatologists) and in a clinical setting where instruments and medications for the management of anaphylaxis are available
The treatment of allergic diseases is based on patient education, allergen avoidance, pharmacotherapy, and AIT
SPT is the gold standard for the detection of allergen sensitization
The treating physicians should be aware of local and regional allergens prevailing in patient's environment
AIT is indicated for the treatment of patients (≥5 years with no limit on the upper age) with allergic rhinitis/conjunctivitis, allergic asthma, and allergic reaction against insect sting/venom. AIT might have positive effects in selected sensitized patients with AD; the best evidence is available for HDM AIT
Age <2 years is an absolute contraindication for AIT while the age of 2–5 years is a relative contraindication for AIT ^[8]
AIT should be used in properly selected cases with a history of precipitation of attack after allergen exposure and positive SPT to clinically relevant allergens. The response of AIT is antigen-specific administered to the patient. Unrelated/irrelevant antigens based on skin text (sensitization) alone should not be included in allergen vaccine
Most of the randomized controlled studies of both SCIT and SLIT are with single allergen extracts
Mixing of allergens (after looking at homologous groups, dose, and compatibility) may be required if the patient suffers from allergic disease due ≥2 clinically relevant allergens
When mixing two allergens from the homologous group, the amount of the individual allergen extract should be equal or select only most important allergen based on highest skin positivity
When mixing allergens from the nonhomologous groups, the amount of individual antigen should be decided depending on their skin test positivity. Compatibility of the allergens (cross-reactivity and enzymatic degradation) should be remembered before mixing allergens
Do not mix allergens with high proteolytic enzyme activities (such as dust mites, fungal, and insects) with any other allergen and prescribe these preferably in separate vials
SCIT and SLIT both have clinical efficacy proven in trials. However, SLIT is currently not approved in India
AIT is used in combination with pharmacotherapy to control the symptoms which would decrease with the increasing efficacy of AIT
AIT should be started at an early age as it has the potential to modify the natural course of allergic disease
AIT can be continued in pregnancy but is usually not initiated in a pregnant woman
Response to AIT starts slowly; however, clinical and physiological improvement has been demonstrated very shortly after the patient reaches a maintenance dose. This should be explained to the patient
If there is no clinical improvement observed after 1 year of therapy, the possible reasons for lack of efficacy with IT should be evaluated. If no reasons are found, discontinuation of IT should be considered, and other treatment options should be pursued
The optimal duration of AIT is still debated. According to reports, AIT can be administered for 3–5 years in patients with a good therapeutic response. However, the decision to discontinue AIT after 5 years should be based on individual patient basis
AIT for food is in the experimental stages and should not be practiced until it has shown to have clinical efficacy and safety
Studies suggest that VIT can be discontinued after 3–5 years in most of the patients. However, decision to discontinue VIT should be taken on the response of patient to treatment
AIT is cost-effective based on clinical response with reduction in medicine requirements and also persistence of benefit for 5–6 years after discontinuation of IT
Skin testing as well as AIT can give severe SR (anaphylaxis) at times. Therefore, skin testing and/or IT should be administered under the supervision of a trained physician who can recognize early symptoms and signs of anaphylaxis and administer requisite treatment in emergency unit
Adrenaline is the drug of choice for IT-induced SRs
Allergens for diagnosis and AIT should be preferably from the same manufacturer
Standardized allergen extracts should be used both for allergy diagnosis and IT to obtain better response. Efforts are required to upgrade the standardization of allergen extracts so that they can be defined in BUs, for example, BAU, AUs, therapeutic unit, standardized BUs. However, in India, following parameters are mandatory for manufacturers – protein content, protein profile, and biopotency
Allergen extracts/vaccine (diagnostic/therapeutic antigen) should be stored at 2°C–8°C and transported using cool device to maintain the allergenic potency.

Acknowledgments

We are thankful to all the core committee members, contributors for providing their valuable inputs in framing the revised guidelines, 2017.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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