Guidelines For Practice of Allergen Immunotherapy in India: 2017-An Update

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Guidelines for practice of allergen
immunotherapy in India: 2017-An
update
S. N. Gaur, Raj Kumar, A. B. Singh, M. K. Agarwal, Naveen Arora
Website:
www.ijaai.in
Abstract:
DOI:
10.4103/ijaai.ijaai_10_17 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
Introduction allergic rhinitis/rhinoconjunctivitis. AIT

can be administered through different
A llergen immunotherapy (AIT) is
an immunomodulatory method
for the treatment of immunoglobulin
routes (subcutaneous, sublingual, oral,
nasal, bronchial, and lymphatic), but
currently, only subcutaneous IT (SCIT)
E (IgE)‑mediated allergic diseases to and sublingual IT (SLIT) have sufficient
control the symptoms and decrease the evidence and therefore are routinely
sensitivity toward allergen(s) by giving used.[1‑3]
sequentially increasing dose of antigen(s)
to induce a shift of the immunological Following the international regulations,
response from TH2 to TH1. Numerous which are also relevant for India, the
terms have been used to describe AIT for practice of AIT should be allowed only
treating allergy, including allergen‑specific to those physicians who have obtained
immunotherapy (IT), specific IT, and specialized training in allergy and AIT and
other terms such as hyposensitization to be practiced at a place where facilities of
and desensitization. [1] The term AIT is managing anaphylaxis are available.
used most recently to refer to the class
Indian College of Allergy, Guidelines for AIT are available in
Asthma and Immunology,
of therapies that aim to induce immune
V. P. Chest Institute, tolerance to allergens. AIT is a therapy with Western/developed countries, [1‑5] but a
University of Delhi, disease‑modifying effects and is currently separate guideline focusing on India is
New Delhi, India used for the treatment of allergic rhinitis, also necessitated due to a multitude of
rhinoconjunctivitis, allergic asthma, and factors. This 2017 update by the Indian
Address for
venom hypersensitivity. It is the only College of Allergy, Asthma, and Applied
correspondence:
Dr. S. N. Gaur, method to prevent the onset/progression Immunology (ICAAI) has been prepared
Director – of asthma in patients suffering from to review the recent data and update
Professor and Head, the guidelines published in 2009.[6] The
Department of Pulmonary This is an open access article distributed under the terms of the
Medicine, Vallabhbhai Creative Commons Attribution-NonCommercial-ShareAlike 3.0
Patel Chest Institute, License, which allows others to remix, tweak, and build upon How to cite this article: Gaur SN, Kumar R, Singh AB,
University of Delhi, the work non-commercially, as long as the author is credited Agarwal MK, Arora N. Guidelines for practice of
New Delhi - 110007, India. and the new creations are licensed under the identical terms. allergen immunotherapy in India: 2017-An update.
E‑mail: sngaur@yahoo. Indian J Allergy Asthma Immunol 2017;31:3-33.
com For reprints contact: reprints@medknow.com
© 2017 Indian Journal of Allergy, Asthma and Immunology | Published by Wolters Kluwer - Medknow 3
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Gaur, et al.: Guidelines: Practice of AIT in India - 2017 update
aim of the current guidelines is to provide clinicians to specific venom, and there is a likelihood of future
comprehensive recommendations on the use of AIT in exposure to the insect. AIT can be lifesaving in such
their daily practice. cases with appropriate antigen. Patients with atopic
dermatitis (AD) due to the aeroallergen house dust
Mechanism of Action mites (HDMs) may also be an appropriate candidates
for AIT [Table 1].[1‑3,5]
Initially, it was presumed that by giving low doses
of same antigen, the immune system produces IgG Patients of allergic rhinitis, of asthma, and with history
antibodies (blocking antibodies) instead of IgE antibodies of symptoms after natural exposure to the allergen
and thus consumes the antigens, resulting in less number demonstrated sIgE antibodies against the offending
of IgE molecules available to produce allergic reaction. allergens. The allergy is assessed by clinical history,
However, the changes in clinical parameters post‑IT did skin tests, and radioallergosorbent test (RAST) or
not always correlate with the changes in IgG or IgE levels. enzyme linked immunosorbent assay (ELISA). AIT
It is now well established with a number of evidence is prescribed for patients ≥5 years with no limit on
that AIT produces a shift of TH2 response toward TH1. the upper age, with symptoms interfering with their
This brings the reduction in release of inflammatory routine work or school performance, causing sleep
mediators, specific IgE (sIgE) levels, and allergen‑specific disturbances, and quality of life (QoL). Patients who
airway hyperresponsiveness apart from producing failed to avoid allergen exposure in spite of all efforts
clinical improvement. There is an increase in specific IgG or had no response to allergen avoidance had poor
levels after AIT. However, initial increase in IgG4 level response to drugs or tired of taking drugs or developed
indicates poor prognosis but that of IgG1 means a better adverse reactions to medicines are most suitable
prognosis. AIT induces a decrease in interleukin‑4 (IL‑4) candidates for AIT. The patients selected must assure
and IL‑5 production by CD4+ TH2 cells and a shift long‑term compliance for the therapy and should not
toward increased interferon gamma (IFN‑γ) production have contraindications for AIT [Table 2].[8]
by TH1 cells. Activation of TH1 subset is associated with
the development of cell‑mediated immunity, essential A shorter disease duration and compliance to AIT
for protective immune response against the development improves clinical outcomes. Table 3 discusses additional
of allergy/asthma. AIT acts by modifying TH4+ T‑cell factors associated with favorable outcomes.[5]
responses either by immune deviation, T‑cell anergy, or
both. Further, a subtype of T‑cells with immunosuppressive Selection of allergens
function and cytokines profiles distinct from their TH1 and The local flora/airborne pollens change approximately
TH2 cells, termed regulation/suppressor T‑cell, have every 200 km distance in India. The soil conditions along
been described. T‑regulatory (Treg) cells producing IL‑10 with environment of the place may affect the protein
and possibly transforming‑growth‑factor beta (TGF‑β), content as well as the antigenicity of the allergens. The
CD4+ CD25+ T‑cells, and TH3 cells play a major role in urban and rural setup as well as the coastal or hilly
the inhibition of allergic disorders. The expression of climate affects the type or antigenicity of the atmospheric
FOXP3 on CD4+ CD25+ T‑cells has also been demonstrated
to correlate with the suppressive capacity of Treg cells Table 1: Indications for allergen immunotherapy
and clinical efficacy following AIT. Figure 1 depicts the IgE‑mediated disease in patients’ ≥5 years with no limit on the
mechanism of action of AIT.[7] upper age (i.e., presence of sensitization on a skin prick test* with
clinical correlation to the symptoms)
Allergic rhinoconjunctivitis
Selection of Patients
Moderate‑severe intermittent rhinitis
Mild to moderate‑severe persistent rhinitis
The success of AIT depends on proper selection of
Allergic asthma (controlled)
patients, allergens, doses, quality of allergens, and
Large local reactions to insect venom
compliance to the treatment. AIT results may reflect
Atopic dermatitis in patients with aeroallergen sensitivity (low level
failure if done by an untrained person. Unnecessary of evidence)
testing, wrong prescription of IT, and taking advantage Symptoms are of sufficient duration and severity
of psychology of patient can lead to adverse reputation Allergen avoidance not possible or if symptom relief is inadequate
in AIT practice.
Availability of standardized or best as technically possible allergen
AIT has proved useful in patients with IgE‑mediated extracts
diseases such as allergic rhinitis, asthma, and insect sting Proof of efficacy of the planned AIT for the respective indication and
hypersensitivity. It should be considered in a patient age group
*In vitro tests may be used only in situations in which skin testing is not
who had history of systemic anaphylaxis reaction after possible and for diagnostic work‑up in children below 5 years. AIT ‑ Allergen
an insect sting and have documented IgE sensitivity immunotherapy
4 Indian Journal of Allergy, Asthma and Immunology - Volume 31, Issue 1, January-June 2017
Figure 1: Mechanism of AIT
Table 2: Contraindications for allergen A document on aeroallergens (pollens) in different

immunotherapy parts of the country has been published[9] and can be
Absolute contraindications Relative consulted to frame the testing kit for patients residing
contraindications in respective area. Physicians/allergologists are
Uncontrolled persistent β‑blockers
also required to consult local aerobiological studies
asthma (FEV1<70% in spite of Cardiovascular diseases
treatment) and studies evaluating the sensitization patterns [9‑33]
HIV (A, B; CD4>200/µL)
Malignant neoplasias published in relevant journals for the prevalence of
Children (2–5 years of
Pregnancy (only for the initiation of AIT) age) airborne pollens, fungi, insects, and mite allergens.
Children (<2 years of age) Psychiatric or mental They can consult the researchers at their nearest botany,
AIDS disorders plant pathology, and entomology departments or attend
Chronic infections training courses in identification of allergens. Relevant
Autoimmune disorders allergens are included in Indian allergen manufacturer’s
Immunodeficiencies or use list, which are mostly common throughout the country.
of immunosuppressives Some of the allergenically important pollens are Prosopis
FEV1 ‑ Forced expiratory volume 1 s, AIT ‑ Allergen immunotherapy,
AIDS ‑ Acquired immunodeficiency syndrome
juliflora, Ricinus communis, Chenopodium album, Cynodon
dactylon, Artemisia species, Alnus nitida, Amaranthus
spinosus, Parthenium hysterophorus, Cassia siamea, and
Table 3: Factors that increase the clinical efficacy of
allergen immunotherapya members of Poaceae. [22] While numerous references
Short duration of disease (early age/initiation of AIT in the course of are available from the different geographical zones of
the disease) India, limited evidence is available from the Himalayan
Minor involvement of the lower airways area.[13,34] Among the Himalaya pollen, a high incidence
Good compliance and adherence with 3-5 years of AIT of skin sensitivity was observed to pollen antigens of
A high cumulative AIT dose (efficacy of immunotherapy is Cedrus deodara, Mallotus philippensis, and Quercus incana
associated with a dose response curve) in patients of Chandigarh residing in the hills and
a
The more of these factors that apply, the higher the probability that
administration of AIT will reduce symptoms and medication use, as well
foothills of the Himalayas while A. nitida, Betula utilis,
as decrease the likelihood of progression of allergic rhinitis to allergic and C. deodara were important sensitizers in New Delhi
bronchial asthma and increase in the number of sensitizations. AIT ‑ Allergen patients. Furthermore, the skin sensitization pattern
immunotherapy
against these pollens was in accordance with the level
of exposure to these pollen of the subjects residing in
pollens in our country. Currently, more data need to that part of the country.[13] Two HDM species, namely
be generated to understand the interplay between the Dermatophagoides pteronyssinus and Dermatophagoides
above‑mentioned factors and allergenic properties. It farinae, are predominant in regions with high humidity,
is essential to select the antigens for testing in a patient especially in coastal areas. Blomia tropicalis is another
based on the above points and confirming the history of important mite species found to be prevalent in tropical
exposure. Besides, it is important to have the knowledge countries and it is found to be prevalent in about 15% of
about the geographical habitat, occupation/residence of Indian patients.[35] Another mite species Acarus siro and
the patient, and also the precipitating factors for his/her Tyrophagus species have also been found to be present
allergic symptoms. in studies published from India.[36‑38] In some patients,
Indian Journal of Allergy, Asthma and Immunology - Volume 31, Issue 1, January-June 2017 5
new antigens for testing may be required decided on Allergen extracts which have been evaluated in Indian
individual basis after surveying patient’s environment. studies include HDMs, pollen, horse dander, insects
(cockroach, mosquito, and housefly), and mixes of
Studies focusing on food sensitizations in India have allergen extracts.
demonstrated the relevance of the following food
allergens in patients with respiratory allergies: Rice, Diagnostic Tests for Detecting Sensitizing
black gram, lentils, citrus fruits, peanut, banana, fish, Allergen(s)
soybean, chicken, wheat, etc., In a study conducted in
New Delhi, patients aged 12–62 years were screened for For AIT of patients with IgE‑mediated respiratory
food allergies using standard questionnaire and skin allergic disorders, identification of specific causative
prick‑test (SPT). sIgE level was determined by ELISA, allergens is of paramount importance. Patient’s history
and allergy was established by blinded food challenges. and clinical examination are the primary modalities
In this study, food allergy is estimated to be 4.5% in for identifying an allergic etiology and identifying the
adolescents and adults with asthma, rhinitis, or both. likely allergens responsible for the allergic symptoms.
Rice, citrus fruits, black gram, and banana were identified The following in vivo and in vitro diagnostic tests are
as major allergens for inducing allergic symptoms.[39] recommended[43‑45] and commonly used:
Furthermore, Indian‑specific data suggest that severe
SPT reactions (4 mm or above) and sIgE, 6.9 ng/ml to rice In vivo tests
are associated with positive blinded food challenge with i. Skin tests (prick and intradermal)[46‑48]
clinical symptoms.[40] Results from the recently published ii. Mucosal challenge tests (bronchial[49] and nasal[50]
EuroPrevall‑INCO study which was conducted in challenge, double‑blind placebo‑controlled food
Karnataka, South India, demonstrated a high level of challenge[51]).
sensitization (26.5%) for most of the foods in the general
population, higher than that observed among adults In vitro tests
It is used for the quantification of total serum
in Europe. The highest prevalence of sensitization to
IgE/allergen‑sIgE levels.
individual foods was observed for shrimp and sesame
i. RAST[52,53]
and was above 13%. However, the prevalence of probable
ii. ELISA
food allergy (self‑reports of adverse symptoms after the
iii. Multi‑allergen screening assays.
consumption of food and sIgE to the same food) was
1.2%, which was mainly accounted for cow’s milk (0.5%) In vivo tests
and apple (0.5%) with very few cases, with probable food
Skin tests
allergy to egg and banana (0.05% each) and to sesame,
Skin tests with inhalant allergens are simple and effective
wheat, and tomato (0.02% each).[41]
method for the identification of causative allergens.
They are the most accurate diagnostic procedures for
Relevant allergens are major contributors to the safety
demonstrating that a specific allergen has induced an
and efficacy of the allergenic extracts used for AIT.
IgE antibody response and are regarded as the gold
Most of the available data address HDMs and selected
standard for the detection of IgE antibodies.[54] Skin
pollens, whereas less is known about the efficacy tests are convenient, simple, biologically relevant,
and safety of mold, animal epithelia, venom, and reproducible, easy and rapid to perform, with low cost
cockroach [Table 4].[3,42] and high sensitivity. Studies indicate that skin testing
might be more sensitive than in vitro tests in detecting
Table 4: Allergens of proven efficacy in allergen allergen‑sIgE.[55‑60] SPTs and intradermal tests vary in
immunotherapy trials globally
sensitivity and specificity, which depends on multiple
Allergen Level of Availability of
factors such as concentration and quality of allergen
evidence data
House dust mite A ++++
solution.
Pollen A ++++
Mold A ++
Preparation of high‑quality allergen extracts is essential
Animal epithelia A ++ for the diagnosis and AIT of allergic disorders.
Hymenoptera A ++ Standardized allergen extracts should be utilized as
venom unstandardized extracts have large batch‑to‑batch
Cockroach B + variability (10–>100 times) and thus may have
A ‑ Evidence from meta‑analysis of RCTs or at least 1 RCT, B ‑ Evidence from variability in the test results.[61] Recently, biological
at least 1 controlled study without randomization or at least 1 other type of
quasi experimental study, ++++ ‑ Multiple long‑term RCTs available, ++ ‑ Few
unit (BU) – used mostly in Europe, and bioequivalent
RCTs available, + ‑ Limited data, RCTs ‑ Randomized controlled trials allergen unit (BAU) – used mostly in the US, have come
to be widely used on standardized products. While the Table 5: Medicines having a suppressant effect on
BU is an in vivo standardization unit based on the SPT the skin prick test
response compared with histamine, the BAU is based Medicine Suppressant
on intradermal skin tests. Furthermore, the global effect
Antihistamines
guidelines also recommend maintenance of an in‑house
Oral first generation >2 days
reference standard, with which all the production H1‑blocker (hydroxyzine, etc.)
batches should be compared using in vitro techniques Oral second generation 7 days
of standardization. H1‑blocker (cetirizine, loratadine, etc.)
Glucocorticoids
A positive control (histamine diphosphate/ Topical (at the test sites) >7 days
dihydrochloride) is always used to ensure (i) that the Systemic short‑term (up to 10 days)
patient is suitable for the performance of skin tests and <50 mg/day prednisolone‑equivalent >3 days
(ii) is not taking any medication (s) which may suppress >50 mg/day prednisolone‑equivalent >7 days
the cutaneous response to injected allergen extracts. Systemic long‑term (>10 days)
Similarly, test with the diluent used to prepare/preserve <10 mg/day prednisolone‑equivalent None
the allergen extracts is also performed as negative control >10 mg/day prednisolone‑equivalent >3 weeks
to rule out the possibility of getting false positive skin Other categories
response due to dermographism or traumatic reactivity Omalizumab[64] 4-6 months
induced by skin test device.[62] Antidepressants
Doxepin 7 days
Skin prick test Desipramine 3 days
The position papers on skin tests by the European Phenothiazine antipsychotics 10 days
Academy of Allergy and Clinical Immunology (EAACI) UV light treatment (PUVA) 4 weeks
UV ‑ Ultraviolet, PUVA ‑ Psoralen and ultraviolet A
and the US Joint Council of Allergy, Asthma and
Immunology (American Academy of Allergy, Asthma
and Immunology [AAAAI], ACAAI) state that properly 100‑fold or 1000‑fold dilution of the concentration used
performed prick test is a most convenient for better for prick test. However, in India, 25–50‑fold dilution
clinical correlation and are economical.[62,63] In addition, of the concentration used for prick tests (1:10/1:20
the World Allergy Organization (WAO) has mentioned weight/volume [w/v]), i.e., 1:500 w/v, has been found
that SPT is the best screening method for detecting sIgE suitable for intradermal tests.[46,48] Intradermal tests are
antibodies.[54] They are highly reproducible when carried more sensitive than SPT testing and thus may provide
out by trained individuals. SPTs are minimally invasive, more false positive results than SPT. Furthermore, they
have high specificity, and have a lower rate of systemic possess a greater risk of systemic reactions (SRs) than
effects as compared to the intradermal tests. SPT is the SPT testing. Therefore, the intradermal tests are generally
gold standard diagnostic method to detect allergen used when percutaneous tests are negative despite an
sensitization. adequate history of exposure and symptoms.[65]
Medicines to avoid before the skin prick tests Mucosal challenge tests
Certain medicines are known to decrease skin Mucosal challenge tests with allergen extracts, both
reactivity, leading to false negative skin tests. bronchial challenge and nasal provocation tests (NPTs),
Clinicians should be aware of the medicines that are of limited clinical value.[49,50] These tests are mostly
could interfere with allergy testing and should counsel used for research purposes as they do not give any
their patients to avoid these to achieve an appropriate significant clinical information, in addition to that
diagnosis [Table 5].[62,64] provided by properly taken clinical history and carefully
performed and graded skin tests.
Medicines which do not have a suppressant effect
on the SPT include intranasal antihistamines, nasal The in vivo methods are summarized below for reference:
and inhaled corticosteroids, leukotriene receptor • Skin tests are followed commonly for allergy
antagonists (montelukast), angiotensin‑converting diagnosis with allergen extracts. The SPT is most
enzyme‑inhibitors, β‑agonists, cyclosporine, H2‑blocker, convenient for better clinical correlation and is a least
theophylline, selective serotonin reuptake inhibitors, and expensive in vivo diagnostic test
selective norepinephrine reuptake inhibitors. • Patient having skin diseases such as eczema,
leukoderma, dermographism, severe dermatitis,
Intradermal test and any other chronic skin disease is not fit for skin
In Western countries, allergen extract solutions for testing, and in case of fever, the test is postponed till
intradermal tests have been recommended to be the patient becomes normal
• For SPT, the allergens are tested in 1:10 or Table 6: Grading for the skin prick test
1:20 w/v dilution, and in intradermal test, Wheal diameter Interpretation
antigens are injected intradermally in 1:500 w/v 0-<3 mm Negative = Negative control
dilution 3-5 mm 1+
• Antigens are administered in the volar aspect of the 6-8 mm 2+ = Positive control
arm or on the back of the patient with a distance of 9-11 mm 3+
5 cm (intradermal) or 3 cm (prick) in between the two >11 mm 4+
Modified.[6,53] The wheal size measured during the SPT should be the mean
tests wheal diameter calculated by taking the sum of the horizontal and transverse
• Globally, the wheal diameter is measured after diameters which is then divided by 2. SPT ‑ Skin prick test
15–20 min and reported in “mm.” A skin reaction
of ≥3 mm than that produced by the negative control Table 7: Grading for the intradermal test
on the SPT is considered as a positive reaction. This Wheal diameter Interpretation
is done to maintain objective assessments of the SPT <6 mm Negative = Negative control (C)
responses[62,63] 2×C 1+
• Qualitative scoring (0–4+; 0 or +) is no longer used 3×C 2+ = Positive control
by many clinicians because of marked interphysician 4×C 3+, with 1-2 pseudopodia
variability in scoring and interpretation of this >4×C 4+, with >2 pseudopodia
method
• The global guidelines do not support the use of To establish atopic status of the patient, total serum
grading the skin response. However, in India, IgE levels are measured.[45] However, the measurement
some clinicians still use the grading system for raised IgE levels are also found in some nonatopic
documenting skin reactions. Grading of skin reaction individuals and in patients suffering with various
is done after 15–20 min in comparison with negative nonallergic diseases. An Indian study has also
control (phosphate buffered saline [PBS]) and positive
concluded that “the IgE levels in Indian allergic patients
control (histamine diphosphate/dihydrochloride).
is significantly related to atopy; however, due to wide
For grading of allergic reaction (skin tests), the
overlap of IgE levels in patients and healthy subjects,
criteria given in Tables 6 and 7 can be followed
its diagnostic significance in Indian population seems
[Tables 6 and 7].[46,53,66]
to be limited.”[67]
The significance of allergen for considering AIT is
considered only if the reaction is equal to or more than Measurement of allergen‑sIgE levels gives reliable
the positive control. information about patients’ clinical sensitivity to
• Physician should be available at the time of skin various aeroallergens. For this purpose, kits based on
testing to take care of any adverse reaction immunoenzymetric techniques commercially available
• In case of high sensitivity (history), skin tests are can be used. Multiallergen screens are useful to support
performed with diluted antigen extracts a more extensive clinical and immunologic investigation
• In case of doubtful reaction, a repeat skin test is for allergic diseases.
performed to confirm the reaction
• Provocation tests with allergen are recommended In vitro tests are considered as a backup tool to SPT
only at the institution level and are mainly done for and should be utilized in cases when the SPT cannot be
research purposes. performed.
In vitro tests Quality assurance is very important for all these in vitro
Most commonly used in vitro diagnostic tests[53] for diagnostic tests. In the USA, external proficiency surveys
the estimation of total IgE and allergen‑sIgE levels are conducted in selected laboratories for checking
in the sera of allergic patients are radio/enzyme uniformity of results using reference samples. In India,
immunoassays. The basic principle remains the there is an urgent need to conduct such surveys to
same, in which a solid phase allergen/antibody binds establish indigenous quality control standards for the
with primary antibody which is further detected measurement of allergen‑sIgE levels.
using a radio/enzyme‑labeled secondary antibody.
The binding signal is converted to a quantitative AIT should not be given only on the basis of the
measurement of concentration using a standard serological tests. In vitro tests may be used only as a
curve, in which one reactant is added in known supportive test or in situations, in which skin testing is
amounts. not possible.
A positive result (either on in vivo or in vitro testing) the maintenance doses may be given in a period of
does not necessarily mean that the symptoms are due to 4–8 weeks, thus reducing the burden of repeated
an IgE‑mediated allergy, and therefore, it is important injections. Randomized trials with accelerated up‑dosing
to correlate results with history and examination of hypoallergenic preparation for pollen have also been
findings. recently conducted, in which the maintenance dose is
achieved in 4 weeks with safety and tolerability profiles
Types of Allergen Immunotherapy comparable to the conventional dose escalation.
Subcutaneous Immunotherapy Rush immunotherapy

The subcutaneous route has been the commonly used The advantage of rush schedule is that patients can
method of administration of AIT. attain the maintenance dose more quickly. Schedule
for rush IT entails administering multiple injection in
Types of allergen extracts a row preferably in a hospital setup. Schedules using
In India, native extracts available as aqueous eight injections over 3 days or 8 injections in a single
preparations are used for SCIT. These allergen day have been published.[71] However, these protocols
extracts are prepared by aqueous extraction of need further investigation in terms of risk and benefit
allergenic materials obtained from natural sources. ratio to patient.
The composition and biologic properties may be
influenced by the quality and purity of the source Cluster immunotherapy
material, as well as their processing, extraction, and The starting dose is similar to those of perennial AIT
storage conditions. In addition to aqueous extracts, regimen. Here, weekly visits are necessary because, at
which are commonly used, depot extracts are primarily each visit, more than one injection is given at a small
used in Europe for SCIT. In Europe, allergens or newer interval between injections, varying from 30 min to 2 h.
hypoallergenic preparations are physically adsorbed After the maintenance dose is reached in approximately
to a carrier, such as aluminum hydroxide (most 2 months, interval between visits is increased. The cluster
common), tyrosine, or calcium phosphate. The regimen is advantageous to the patients who reside
concept of hypoallergenic preparations is that they at a significant distance from a physician. There are
possess less reactive B‑cell epitopes and thus reduce similar efficacy and immunological changes in cluster
IgE binding, while their T‑cell epitopes and their regimen as observed with the perennial IT in various
immunogenic effect remain unaltered.[68,69] In Europe, studies.[72] However, the initial doses are required to be
these hypoallergenic preparations comprise up to 50% given in a hospital set up able to manage emergencies
of the SCIT prescriptions.[70] Numerous studies have associated with this form of therapy. Cluster schedule
provided clinical efficacy and safety of the allergen with hypoallergenic mite‑SCIT has also been developed
extracts. Advantages of hypoallergenic preparations and is found to be safe and well‑tolerated in routine
are lesser SRs, shorter dose build‑up phase, and less clinical practice.
frequent dosing.
Sublingual immunotherapy
Administration regimens The sublingual route has attracted the greatest interest
Conventional regimen in recent years as shown by the number of double‑blind,
Currently, in India, only aqueous extracts are available. placebo‑controlled trials and the fact that SLIT has
In most of the cases, AIT is started with 1:5000 w/v spread widely in some countries in Europe. However,
diluted antigen and the injections are given two times further studies are needed to define the most appropriate
a week starting from and increased by 0.1 ml in every dosage, the efficacy in pediatric patients, and to evaluate
injections. The injections are given subcutaneously the magnitude of efficacy compared to other available
with graduated syringe or insulin syringe. The idea is treatments.[73‑76]
to achieve the highest maintenance dose, i.e., 1:50 – one
time a month, 1.0 ml. Usually, the maintenance dose is In contrast to the subcutaneous route, SLIT requires a much
between 0.5 and 1.0 ml of 1:50 dilution. In cases showing higher amount of antigen to achieve clinical efficacy. On an
high skin sensitivity with local reaction (LR)/SR after average, SLIT requires at least 50–100 times more allergen
initiation (1:5000 w/v) of AIT, it is rescheduled/started content than SCIT to be efficacious, and consequently,
with higher dilution, i.e., 1:50,000 w/v or even higher low‑dose SLIT is generally ineffective.[77] Furthermore, in
dilution, and the first injection is administered in the comparison with SCIT (which is standardized in regimens
hospital/clinic having facilities to manage anaphylaxis. and protocols), SLIT is affected by numerous variables
[Table 8]. It can be administered as drops, mono‑dose
Fewer buildup injections are possible with the depot vials, or tablets and with variable timings and doses. In
and hypoallergenic formulations. Furthermore, particular, the maintenance dose is strictly dependent on
Table 8: Evidence of head‑to‑head comparison of Additional approaches to AIT under active investigation
subcutaneous versus sublingual immunotherapy include epicutaneous and intralymphatic administration.
Study Number of Treatment favoured A few clinical trials with intralymphatic route have
participants Asthma Rhinitis/ indicated that this route is efficacious and safe with a
symptoms rhinoconjunctivitis limited number of injections.[78]
symptoms
Mungan, 1999 36 SCIT None
Yukselen, 2011 31 SCIT SCIT Duration of Allergen Immunotherapy
Eifan, 2010 48 SLIT SCIT
Keles, 2011 56 SCIT SCIT
AIT is generally administered for 3–5 years; the
Khinchi, 2004 48 ‑ SCIT duration and decision to discontinue it must be
Tahamile, 2006 193 ‑ SCIT individualized. Some patients may require longer
SCIT ‑ Subcutaneous immunotherapy, SLIT ‑ Sublingual immunotherapy periods of treatment. It is difficult to predict that
how long patients will experience symptomatic relief
the method of standardization, which varies from one following discontinuation of AIT. However, prolonged
manufacturer to another.[78] remission of symptoms after discontinuation has been
documented in prospective studies with grass pollen
In addition to above‑mentioned points of variability in SCIT for allergic rhinitis and HDM SCIT for asthmatic
the doses, SLIT has also been clinically effective only for patients.[92,93]
a limited number of allergens.
Clinical benefits which are ongoing have been
SLIT is currently not approved in India but is under documented 12 years after discontinuation of AIT
consideration of the drug regulatory authority. as compared to pharmacotherapy only (please see
the section on “Preventive and Disease Modifying
Other routes Capacity” for further details). The clinical benefits may
depend on the nature of the allergen extracts.
Bronchial immunotherapy
A limited number of clinical trials have been carried
out using this route of administration.[79,80] The results Assessing the Response to Allergen
obtained were unimpressive in terms of efficacy, and Immunotherapy
the bronchospasm was induced in many of the patients
treated. Therefore, this route of administration has been The assessment of the response to AIT is made
abandoned in view of an unfavorable risk–benefit ratio. clinically by the improvement of symptoms and
reduction for the need of medications (symptom score,
Oral immunotherapy medication score, or combined symptom medication
scores [CSMSs]) and assessment of QoL. Tests such
Although a greater number of clinical trials with a
as quantitative SPT, bronchial hyperresponsiveness
suitable design[81] have been carried out using this route
test, and immunological parameters may also be
of administration, a few of them achieved an acceptable
used. However, these parameters may not always
level of clinical efficacy. [82,83] In some trials, [84,85] the
correlate with improvement in allergic disease status
effect was no better than that of placebo. Furthermore,
of patients. Measurement of total IgE has no value for
adverse events including abdominal pain, vomiting,
such assessment.[2,3]
and diarrhea were recorded in some studies.[85,86] The
present results do not support the oral route as an Nonquantitative skin testing (demonstrating skin test
effective alternative.[87] reactivity to a single dilution) or serum‑sIgE antibody
testing of patients during AIT is not recommended
Nasal immunotherapy because it has not been demonstrated that they correlate
Twenty‑two studies of intranasal administered AIT with a patient’s clinical response. Efficacy and clinical
have been evaluated.[88] Sixteen used a double‑blind, contraindications should be assessed regularly. [2,3]
placebo‑controlled design. Most of these trials Studies have shown that AIT inhibits allergen‑driven
demonstrated significant clinical efficacy in allergic TH2 response, so the cytokines typical for TH1 versus
rhinitis. The results are encouraging, but nasal AIT TH2 responses could be used as markers to judge the
seems to be a treatment for allergic rhinitis only. Some response of AIT. The immunological markers such as
studies also reported local adverse effects.[89,90] The only Treg cells with increase in IL‑10 and IgG4 blocking
study addressing long‑term efficacy demonstrated antibody) correlate well with reduction in immediate
no sustained effect, following discontinuation of the skin test response and decrease in late phase response,
treatment.[91] There are no data on the possible preventive which may be used to assess the response and to decide
capacity. when to stop AIT.[94]
In summary, clinical parameters (such as symptom seasonal allergic rhinitis and in patients suffering with
score, medication score, or CSMSs) and assessment of perennial allergic rhinitis. Hence, subcutaneous AIT
QoL shall be considered to assess the response to IT. was approved for the management of allergic rhinitis
and/or allergic asthma. However, AIT is currently
Efficacy: Immunotherapy Trials Including indicated as a supplement to allergen avoidance and to
pharmacotherapy.[103] Its efficacy in the prevention of
Cochrane Database Analysis
allergic march and the development of asthma among
patients with allergic rhinitis has been demonstrated.[104,105]
Subcutaneous immunotherapy
SCIT is effective in the treatment of allergic rhinitis, Data were extracted from 16 studies showing clinical
allergic conjunctivitis, and allergic asthma, in both effectiveness of SCIT in the treatment of allergic rhinitis,
children and adults. It is also used in the treatment of involving 759 patients (546 adults, 53 children, 160 all
venom hypersensitivity, which is discussed separately. ages). In 15 (94%) of the studies, SCIT led to significant
The parameters that indicate clinical efficacy of a improvement in both symptoms and medication scores.[94]
treatment are reduction in symptoms and/or drug Its efficacy has been validated in many trials, using grass,
intake of a magnitude that significantly reduces ragweed, and birch pollen extracts.[96] Importantly, SCIT
morbidity.[95] The clinical efficacy of SCIT has been has been shown to be effective even in patients with
validated in numerous clinical trials in children and severe seasonal rhinitis that is resistant to conventional
adults. Clinical efficacy has been confirmed for allergen drug therapy. There was a highly significant decrease
products from birch, grasses, mountain cedar, cypress, versus median placebo (95% confidence interval [CI]
olive, Parietaria, ragweed, cat, D. pteronyssinus, Alternaria, for difference between medians) in total symptom
and Cladosporium. scores (P = 0.001), total drug use (P = 0.002), and
visual analog symptom scores (P = 0.02), 2.2 versus 5.5
Fundamental questions on AIT are (1) whether it (−4.8–−0.5). Provocation tests after allergen IT showed a
has potential to provide long‑term benefit following greater than 10‑fold reduction in immediate conjunctival
its discontinuation and (2) whether it can prevent allergen sensitivity (P = 0.001), a 40% decrease in early
either disease progression or the onset of new allergic phase response (P = 0.02), and a 57% decrease in the late
sensitivities.[96] Without long‑term reduction in disease phase (P = 0.001) cutaneous response after intradermal
severity and disease‑modifying capability, AIT may allergen challenge.[98]
not be cost‑effective and consequently not be a real
alternative to pharmacologic treatment. [97] Previous A Cochrane review, on the meta‑analysis of 51
studies on IT indicate that the treatment may have a randomized double‑blind placebo controlled trials
long‑lasting effect. A controlled study by Durham et al.[92] involving 2871 subjects with seasonal allergic rhinitis
has documented the long‑term efficacy of AIT after or controls, has shown that AIT results in significant
withdrawal of the treatment, following a double‑blind, improvement in overall symptoms, medication use, and
placebo‑controlled trial.[98] QoL. Symptom score data from 15 trials were suitable
for meta‑analysis and showed an overall reduction in
As per the WHO[99] and AAAAI recommendations,[3] the AIT group (standardized mean difference [SMD]
at present, allergen avoidance and IT are the only −0.73 [95% CI − 0.97–−0.50, P < 0.00001]). Medication
treatments that modify the course of an allergic score data from 13 trials showed an overall reduction
disease either by preventing the development of new in the AIT group (SMD of − 0.57 [95% CI − 0.82–−0.33,
sensitivity or by altering the natural history of disease P < 0.00001]). Adrenaline was given in 0.13% (19 of 14,085
or disease progression. The optimal dose for SCIT has injections) of those on active treatment and in 0.01% (1 of
been recommended as the maintenance target dose 8278 injections) of the placebo group for treatment of
for all patients. Doses of 5–20 micrograms of the major adverse events. There were no fatalities.[106,107]
allergen are optimal doses for domestic mites, cat dander,
ragweed pollen, and hymenoptera venoms. These doses A current meta‑analysis (2013) evaluated 17 clinical
are tolerated by the majority of patients with allergic trials (up to April 2011) for the efficacy of SCIT in
diseases without difficulty. patients with seasonal allergic rhinitis.[108] This analysis
found a reduction in the symptom scores (SMD − 0.65;
Allergic rhinitis 95% CI − 0.85–−0.45; P < 0.00001; all 17 studies), the
AIT alters allergic disease through a series of injections medication scores (SMD − 0.55; 95% CI − 0.75–−0.34;
of clinically relevant allergens and has been recognized P < 0.00001; 16 studies), the CSMSs (SMD − 0.48; 95%
as the only therapeutic option known to alter the CI − 0.67–−0.29; P < 0.00001; 8 studies) as well as an
natural history of allergic rhinitis.[100,101] According improvement in the QoL scores (SMD − 0.53; 95%
to the AAAAI,[102] AIT is successful in patients with CI − 0.66–−0.39; P < 0.00001; 8 studies).
The benefits of AIT for perennial rhinitis are less than CI 3–6) with IT to avoid one requiring increased
for seasonal rhinitis. In part, this reflects the difficulty in medication. AIT significantly reduced allergen‑specific
determining the extent to which allergy is responsible bronchial hyperreactivity, with some reduction in
for perennial symptoms. Nevertheless, clinical trials nonspecific bronchial hyperreactivity as well. There was
have shown a definite benefit in appropriately selected no consistent effect on lung function. If 16 patients were
subjects. [109] Clearer evidence has been obtained in treated with IT, one would be expected to develop a local
perennial rhinitis due to pet allergy. Several studies adverse reaction. If nine patients were treated with IT,
have shown a marked improvement in tolerance of cat one would be expected to develop a SR (of any severity).
exposure after SIT, validated both on challenge tests and
simulated natural exposure.[110] A recently published meta‑analysis evaluated the
efficacy and safety of SCIT in mite‑sensitized subjects
Bronchial asthma with asthma.[121] A total of 796 subjects from 19 different
A meta‑analysis of 75 SCIT trials concluded that there randomized controlled trials (RCTs) were included in
is a significant reduction in asthma symptoms and drug this analysis. SCIT significantly reduced the asthma
requirement as well as in bronchial hyperreactivity with symptom scores (SMD − 0.94, 95% CI − 1.58–−0.29,
SCIT.[111] SCIT has been found to maintain a persistent P = 0.004) and the asthma medication scores (SMD − 1.06,
improvement after discontinuation of IT [92,105,112,113] 95% CI − 1.70–−0.42, P = 0.001) compared with the
and also reduces the risk of future development of control group. One study conducted solely in children
asthma in rhinitis cases. [92,94,105,113‑116] Successful IT with allergic asthma, in which SCIT was employed using
prevents development of new allergen sensitivities in an hypoallergenic extract of HDM, showed improved
monosensitized individuals.[117‑119] asthma control as well as significant reduction in the
required doses of inhaled corticosteroids compared with
A 2003 Cochrane review included 75 trials with a the control group not treated with SCIT.[122]
total of 3506 participants (3188 with asthma) for data
analysis in a meta‑analysis.[111] There were 36 trials A meta‑analysis prepared by the Johns Hopkins
of HDM allergy, 20 pollen allergy, 10 animal dander University Evidence‑based Practice Center for the
allergy, 2 Cladosporium mold allergy, 1 latex, and 6 Agency for Healthcare Research and Quality (AHRQ,
for multiple allergens. Concealment of allocation was USA) included 74 references that investigated the
assessed as clearly adequate in only 15 of these trials. efficacy and safety of SCIT.[123] In this meta‑analysis, the
Significant heterogeneity was present in a number of strength of evidence was high that SCIT reduces asthma
comparisons. Overall, there was a significant reduction symptoms, rhinitis symptoms, conjunctivitis symptoms,
in asthma symptoms and medication and improvement asthma medication use, asthma plus rhinoconjunctivitis
in bronchial hyperreactivity following AIT. Furthermore, medication use, and rhinoconjunctivitis‑specific QoL.
a significant improvement was therein asthma symptom The strength of evidence is moderate that SCIT reduces
scores (SMD − 0.72, 95% CI − 0.99–−0.33) and it would rhinoconjunctivitis medication use, relative to usual care,
have been necessary to treat 4 (95% CI 3–5) patients with which includes pharmacotherapy.
SCIT to avoid one deterioration in increased medication.
AIT significantly reduced allergen‑specific bronchial Atopic dermatitis
hyperreactivity, with some reduction in nonspecific AD may respond to SCIT if the patient is sensitized to
bronchial hyperreactivity as well. However, there was inhalant allergens although this conclusion is based on
no consistent effect on lung function. a small number of studies[3] of HDM allergic patients,
including one randomized trial of 51 patients.[124,125]
The 2010 updated Cochrane meta‑analysis “Injection Negative studies also exist.[126] The impact of IT on AD
allergen IT for asthma” included 88 trials (13 new in patients sensitized to pollens or other aeroallergens
trials).[120] There were 42 trials of IT for house mite has not been studied. Thus, the use of SCIT to treat AD
allergy; 27 pollen allergy trials; 10 animal dander requires careful observation of the patient’s clinical
allergy trials; two Cladosporium mold allergy, 2 latex, status, especially during the buildup phase of treatment.
and 6 trials looking at multiple allergens. Overall, One randomized double‑blind dose‑range finding
there was a significant reduction in asthma symptoms SCIT trial on 89 adult patients with a chronic form of
and medication and improvement in bronchial AD and sensitization to HDMs revealed a significant
hyperreactivity following AIT. There was a significant improvement of the scoring atopic dermatitis (SCORAD)
improvement in asthma symptom scores (SMD − 0.59, over a 1‑year therapy course.[125] In a more recently
95% CI − 0.83–−0.35 [P < 0.00001]) and it would have been published DBPC‑Phase‑III study (SCIT) on 168 adult
necessary to treat three patients (95% CI 3–5) with IT to patients, a significant improvement in the SCORAD was
avoid one deterioration in asthma symptoms. Overall, only demonstrated in a subgroup with severe forms of
it would have been necessary to treat four patients (95% AD.[127]
Preventive and disease modifying capacity for preventing than for curing asthma. Further studies
The capacity of SCIT to prevent the development are needed to clearly define the preventive capacity
of new sensitizations has been investigated in of SCIT.
three nonrandomized studies in monosensitized
patients. [117‑119] In an open retrospective study, Studies on Sublingual Immunotherapy
Purello‑D’Ambrosio made a follow‑up of 7182
monosensitized (to different allergens) patients treated Due to new controlled trials in adults [131‑137] and
with SCIT for 4 years and off IT for 3 years.[118] The children,[138‑140] some with high patient numbers, data
control group consisted of 1214 matched patients on the efficacy of SLIT are also available. SLIT has been
followed for 7 years. The development of sensitization suggested to be a particularly attractive treatment for
to new allergens showed a clinically relevant and children where safety is paramount and outpatient, and
statistically significant difference at the 4‑year home‑based therapy is clearly preferable. However, more
follow‑up, with figures of 68% in the control group studies in children are urgently required because several
versus 24% in the IT group and at the 7‑year follow‑up issues remain unsolved: for example, optimal doses
78% and 27%, respectively. Pajno et al. followed 75 and duration of treatment in children, the evaluation of
SCIT‑treated children monosensitized to HDMs and quality‑of‑life and compliance with administration, of
63 comparable controls treated pharmacologically vaccine at home. Besides, storage of the allergen product
for 6 years.[119] In the IT group, 74% continued to be during the time family is out of home, for example,
monosensitized versus 33% in the control group. during holidays and dosing during acute, but prolonged
A prospective controlled prolonged follow‑up study gastroenteritis also required to be investigated. The
demonstrated the ongoing clinical benefit 12 years after excellent safety profile of SLIT and the fact that injections
discontinuation of hypoallergenic AIT as compared to are not required with this approach raise the possibility
pharmacotherapy only. Furthermore, the reduction in that SLIT could be given to children below the age of
onset of new sensitization (58% in the AIT group and 5 years, in an attempt to modify the natural course of the
100% in the control group) is sustained at the 12‑year allergic disease. However, definitive trials are required
follow‑up. In addition, there was a tendency for lower to achieve this objective.[141,142]
prevalence of seasonal asthma in the post‑AIT group.[105]
Although these studies are of interest, prospective Allergic rhinitis
randomized, controlled studies are needed. A meta‑analysis published by the Cochrane Library
on the clinical efficacy of SLIT in patients with rhinitis
In India, a double‑blind placebo‑controlled study included 22 double‑blind, placebo‑controlled clinical
showed significant improvement in clinicoimmunologic trials, and a total of 979 patients.[143] There was significant
parameters in asthma and rhinitis patients after heterogeneity for most comparisons, likely due to the
1 year of IT with whole‑body mosquito extract.[128] A use of several alternative scoring systems in different
placebo‑controlled study demonstrated early relapse of studies. However, results showed a significant reduction
symptoms after discontinuation of treatment in patients in rhinitis symptoms and medication requirements. Out
receiving pharmacotherapy, whereas it was 3–5 years in of 22 studies, 12 included children <15 years whereas
IT group patients.[129] four studies were conducted exclusively in children. The
doses of allergen used in different studies were analyzed
SCIT might prevent the progression of rhinitis into by Canonica and Passalacqua[88] that ranged from 3–5 to
asthma. A multicenter pediatric study investigated 375 times the cumulative dose of SCIT. There was no
the capacity of IT in children with allergic rhinitis to clear relationship between the dose administered and
downregulate the development of asthma.[130] Children clinical efficacy; hence, more dose–response studies are
allergic to birch and grass pollen and no symptoms needed to clearly indicate the optimal therapeutic dose.
of lower airway hyperreactivity were randomized to A dose–response relationship has been analyzed for
pharmacologic treatment. After 3 years of treatment, ragweed extract.[144]
the number of children developing clinical asthma was
statistically reduced in the IT group. The development The 2010 Cochrane update[145] included for the symptom
of asthma was in 24% children in IT group versus scores 23 studies in grass pollen allergic patients
44% in the drug‑treated group, indicating high (SMD − 0.35; 95% CI − 0.45–−0.24; P < 0.00001), 9 studies
risk of developing asthmatic symptoms in allergic (including 2 using birch pollen extract) in tree pollen
rhinitis children is diminished by IT. Bronchial allergic patients (SMD − 0.42; 95% CI − 0.77–−0,06;
hyperresponsiveness to methacholine decreased P = 0.02), and 9 studies in HDM allergic patients
significantly in IT‑treated children, but only 2 out of 40 (SMD − 0.97; 95% CI − 1.80–−0.13; P = 0.02). For the use
children with asthma at inclusion were free of asthma of SLIT in AR, the Cochrane meta‑analysis found an
after 3 years, indicating that IT has a greater capacity advantage for AIT for all allergens (P < 0.00001).
A meta‑analysis published earlier this year (2015) The long‑term effect of SLIT was investigated in an
assessed the efficacy and safety of the grass pollen open controlled study including 60 mite‑sensitive
sublingual tablets licensed as drugs in the treatment asthmatic children aged 3–17 years.[156] Allocation to
of patients with seasonal allergic rhinoconjunctivitis IT or pharmacotherapy group was based on parental
to grass pollen.[146] Data were available in 13 RCTs for preference. SLIT was given for 4–5 years and the
the symptom score (4659 patients) and in 12 RCTs children followed up for 10 years. At 10 years, there
for the medication score (4558 patients). The authors was a significant reduction in the onset of asthma, use of
found a small treatment benefit in the symptom score asthma medication, and an increase in peak expiratory
(SMD, −0.28; 95% CI, −0.37–−0.19; P < 0.001) and in the flow rate as compared to control group.
medication score (SMD, −0.24; 95% CI, −0.31–−0.17;
P < 0.001) and concluded that considering the low Allergens to be used for SLIT are limited and no
magnitude of the benefit, the convenience and easy Indian clinical trial data on SLIT (i.e., randomized
administration do not seem to be sufficient reasons for double‑blind placebo‑controlled studies) are available.
the choice of SLIT. The dosage of SLIT also ranges from 50‑fold to 100‑fold
compared to the doses which are commonly given
Allergic asthma for SCIT. In addition, different manufacturers have
Compared with allergic rhinoconjunctivitis, there are different doses for the SLIT allergens which are not
only a limited number of studies on the efficacy of comparable.
SLIT in patients with allergic bronchial asthma. The
2006 Cochrane Collaboration method meta‑analysis The summary of efficacy data for allergen immunotherapy
data found no significance (P = 0.07) for the use of from Cochrane Reviews/meta-analysis is shown in
SLIT in allergic asthma.[147] A grass tablet study showed Figure 2.[120,145,147,158]
efficacy for SLIT in bronchial asthma in a subgroup of
children with seasonal allergic asthma.[138] With regard Studies Comparing Sublingual and
to IT using dust mite extracts, heterogeneous results
were found in clinical trials with methodological
Subcutaneous Immunotherapy
limitations.[148‑151]
Both the routes of administration, SCIT and SLIT,
have shown efficacy and safety in clinical trials and
A recent study included 604 HDM allergic patients at
least 14 years of age with mild to moderate asthma meta‑analyses. There are few trials and meta‑analyses
treated for a 1‑year period with SLIT with HDM tablets. which have compared that there are two routes of
Compared with placebo, actively treated patients administration.
exhibited a significant reduction in the dose of inhaled
The meta‑analysis prepared by the Johns Hopkins
corticosteroids required to maintain asthma control over
University Evidence‑based Practice Center for the
the course of the study period.[152]
AHRQ, USA, investigated the efficacy and safety of
A meta‑analysis published in September 2015 evaluated subcutaneous and SLIT.[123] The researchers reviewed
a total of 454 children with asthma/rhinitis who were the head‑to‑head comparative trials of the two routes
sensitized to HDMs and were treated with SLIT or of administration [Table 8].[123] The analyses revealed:
control for between 4 months and 3 years.[153] The analysis • For allergic asthma symptom control: The studies
indicated that dust mite SLIT therapy was effective in support SCIT over SLIT (strength of evidence, low
reducing asthma symptoms and in increasing sIgG4 but [4 studies, n = 171])
did not significantly reduce medication scores or specific • For allergic nasal and/or eye symptoms: The strength
D. pteronyssinus IgE levels. The authors noted that the of evidence was moderate that SCIT is more effective
data are not enough to support the use of dust mite SLIT than SLIT for reducing allergic nasal and/or eye
in children with asthma. symptoms (6 RCTs, n = 412)
• The data were inadequate to comment on reduction of
Preventive and disease‑modifying capacity medication use, symptom and medication reduction,
A randomized controlled open SLIT study in children has and QoL. The strength of evidence lowly favors SCIT
shown preventive effect on asthma onset.[154] In control for reducing asthma symptoms and for controling
group, 18 of 44 developed asthma versus 8 of 45 in the nasal and eye symptoms.
sublingual group after 3 years of treatment. Another
randomized controlled open study demonstrated the Other systematic reviews which have compared the two
prevention of new sensitizations in a 3‑year long trial[155] routes of administration (i.e., SCIT and SLIT) are detailed
whereas this effect was not observed in another open in Table 9.[159] These include the studies in adult as well
study.[156,157] as the pediatric population.
Table 9: Systematic reviews comparing subcutaneous and sublingual immunotherapy

Key findings Chelladurai, 2013 Kim, 2013
Number of RCTs 8 SCIT versus SLIT 3 SCIT vs. SLIT (only pediatric)
Symptom score Favors SCIT (moderate‑grade evidence) Favors SCIT (low‑grade
evidence)
Medication score No difference (low‑grade evidence) Favors SCIT (low‑grade
evidence)
Safety (reactions) Local (frequency): SCIT: 20%; SLIT: Local (patients): SCIT: 3; SLIT:
7%-56% 3
Anaphylactic: SCIT: 1; SLIT: 0 Systemic (patients): SCIT: 4;
SLIT: 0
Anaphylactic: SCIT: 1; SLIT: 0
SCIT ‑ Subcutaneous immunotherapy, SLIT ‑ Sublingual immunotherapy, RCTs ‑ Randomized controlled trials
Figure 2: Summary of efficacy data for allergen immunotherapy from Cochrane reviews[120,145,147,158]
Systematic reviews and meta‑analyses of RCTs of reactions on re‑sting challenge. In the prospective
SCIT, SLIT, or both versus placebo (indirect and uncontrolled studies, only 0%–9% of vespid allergic
direct comparison) suggest that SCIT might provide and around 20% of bee venom allergic patients reacted
greater clinical and immunologic efficacy. However, to challenge with the respective insect. These studies
more studies with a greater number of patients are suggest the superior efficacy for IT with vespid or ant
needed to evaluate the magnitude of the clinical venom compared to honey bee venom. The patients who
efficacy and the optimal dosage. Regarding the final reacted following a course of VIT had mild symptoms
choice between SCIT and SLIT, the decision needs to than those observed before the treatment. VIT is effective
be made individually with each patient after careful in 95% of patients allergic to wasp venom and about 80%
considerations of factors. of those allergic to bee venom.[164]
The safety of VIT is related to the nature of the venom

Venom Immunotherapy used and the protocol. More side effects were observed
during IT with honey bee venom than vespid venom.[165]
The efficacy of venom IT (VIT) has been analyzed in three
In an EAACI multicenter study of 840 patients totaling
controlled and several prospective uncontrolled studies 26,601 injections, 20% of patients developed mild
which employed a usual maintenance dose of 100 µg of systemic allergic reactions, corresponding to 1.9%
venom.[160‑162] In these studies, patients were monitored of injections during the dose increase phase and
with sting provocation tests during IT.[163] In all controlled 0.5% during the maintenance phase.[166] Rapid dose
trials with vespid, honey bee, or ant venom allergy, increase, especially with high cumulative daily doses of
comparing venom with either whole‑body extract or 200–500 µg in rush protocols, may increase the risk of
placebo, a highly significant difference was observed in side effects. In patients who cannot safely discontinue
favor of VIT. Here, 75%–100% of venom‑treated patients β‑blockers but who have a history of moderate to severe
tolerated re‑sting without any allergic symptoms, while sting‑induced anaphylaxis, VIT is indicated because the
64%–75% of whole‑body product and 58%–72% of risk of anaphylaxis related to a venom sting is greater
placebo‑treated patients developed systemic allergic than the risk of an IT‑related SR.[3]
Allergen Immunotherapy Studies in India allergic conjunctivitis. Sixty‑two percent of these showed
beneficial response as documented by the symptoms and
A limited number of studies are available on AIT medications scores.[175] In India, a preliminary observation
from our country. [128,129,167‑169] IT for 1 year in cases has documented the steroid‑sparing effect of cluster
of asthma and/or rhinitis has demonstrated >50% IT combined with anti‑IgE, the combination being also
improvement in clinical parameters (symptoms).[167] A associated with good tolerability.[176]
placebo‑controlled study on AIT for 6–12 months with
Cocos nucifera pollen extract showed significant clinical A retrospective analysis of a prospective symptom review
improvement (symptom‑medication score), reduction in patients receiving AIT has been conducted in India to
in IgE, and elevation of specific IgG in posttherapeutic determine the type of allergens, number of allergens, and
patients’ sera than placebo.[168] Another study evaluated concentration of the allergens or the combination on the
the immunological changes that follow SCIT in patients efficacy of AIT. Patients received AIT with a mixture of
suffering from bronchial allergy and/or allergic rhinitis. 5–8 allergens and HDM was administered separately. The
The inflammatory makers (IL‑5 and IL‑6 levels) at 0, 3, authors found that only 42% of their patients improved
and 6 months were compared, and it was noted that with while 58% had no improvement or had worsening of
an increase in duration of treatment, the levels of these their symptoms. It was observed that 58% of the patients,
markers decrease significantly (P = 0.003).[170] who did not benefit from AIT, received the incorrect
combination of allergens. The compatibility of allergens
An open comparative study of IT versus budesonide was based on the protease activity of the individual
inhalation has reported almost equal improvement in allergens. High protease‑containing enzymes included
asthma patients in both the groups.[129] However, the dust mites, fungal, and insect allergens. These results
decline in benefit was rapid in drug treatment group clearly lay emphasis on the nature of allergens and their
than AIT after cessation of treatment. Another study combination used for IT. Furthermore, the inclusion of
determined the efficacy of HDM IT over a 15‑year all allergens to which IgE antibodies are present, without
period. [171] The use of IT resulted in a statistically establishing the possible clinical relevance of these
significant improvement in both global symptom scores allergens, dilutes the content of other allergens in the
and forced expiratory volume 1 s in patients receiving vaccine and can make AIT less effective.[177] A double‑blind
IT when compared with those in the control group who placebo‑controlled study evaluated the efficacy of single
did not receive IT. This improvement was sustained insect extract (cockroach, housefly, or mosquito) and mix
for at least 10 years after cessation of IT.[171] Another allergen IT (two or three insect extracts) with placebo.
observation presented the ongoing clinical benefit for In this study of insect AIT, mixed and/or single insect
6–9 years in 35 patients even after discontinuation of AIT for 1 year demonstrated significant improvement in
HDM (D. farinae/D. pteronyssinus) SCIT for 3 years.[172] clinical (skin reactivity, airway reactivity, and symptom
score) and immunological (IgE/IgG4 and IgG1/IgG4
A recent double‑blind placebo‑controlled study on ratio) parameters.[169]
AIT with mosquito extract in asthma and allergic
rhinitis patients has demonstrated significant clinical Another study – a double‑blind, placebo‑controlled trial
improvement, supported with changes in airway reactivity of cockroach AIT performed for 1 year in fifty patients
and immunologic parameters (IgE, IgG1, IgG4, and IFN‑γ) of asthma, rhinitis, or both – evaluated the efficacy of
from the baseline and placebo.[128] Further, AIT with two AIT by change in skin reactivity and clinical parameters
to three mix extracts from the same allergen group is such as symptom/drug score, airway reactivity, and
effective for insect hypersensitivity.[169] A double‑blind, immunological parameters. AIT with cockroach extract
placebo‑controlled trial of cockroach AIT was performed demonstrated significant improvement in clinical
for 1 year in fifty patients of asthma, rhinitis, or both. parameters of active group patients compared with
AIT with cockroach extract improved clinical and baseline values and placebo group. sIgE levels showed
immunological status of asthma and rhinitis patients.[128] A a modest reduction, while IgG4 levels increased
case study has also documented the successful SCIT with significantly in active AIT group after 1 year. IgE
horse dander allergy in a patient with recurrent episodes immunoblotting demonstrated reduction in intensity
of anaphylaxis on coming in contact with horse.[173] An and number of specific bands, whereas IgG4 binding
open‑label study evaluated the efficacy of swallow SLIT showed more number and distinct bands following
and rush SCIT (25 patients in each group, with allergic AIT. Active group patients showed correlation between
rhinitis, asthma, or both) using randomization technique increase in IgG4/IgG1 ratio and reduction in symptom
and followed up for 1 year.[174] There was significant score post‑AIT.[178]
improvement in QoL in both SLIT and rush SCIT
groups from baseline to end of 1 year. Another study A prospective nonrandomized with 6‑year follow‑up study
evaluated the response to AIT in eighty patients with evaluated the safety of SLIT in pregnancy in Indian patients.
One hundred and fifty‑five patients received SLIT with Table 10: Risk factors for systemic reactions during
either HDM (D. farinae) or a mixture of up to five allergens allergen immunotherapy
during 185 pregnancies.[179] Two control groups did not Current allergy symptoms and potential allergen exposure
receive IT; Group A (85 patients) received budesonide Current infections
400 µg twice daily and Group B (40 patients) received rescue Mast cell disease
Hyperthyroidism
salbutamol inhalation. In this study, there were no episodes
Unstable or insufficiently treated asthma
of SRs, but there were 11 episodes of LRs (oral) to SLIT,
A high degree of sensitization
consisting of mild itching in the oral cavity and/or swelling
Inadequate dose escalation during initiation
of lips. Patients, in whom LRs were noted, delivered
Pharmaceutical use (β‑blockers)
normally. The incidence of abortion in the salbutamol group
Inadequate circulatory stress, excessive alcohol consumption,
was higher than in the general population (P < 0.05) and high‑intensity physical exercise, sauna (shortly before and for the
was higher in both control groups when compared with rest of the day of injection, augmenting factors should be avoided)
the SLIT group (P < 0.05). The incidence of perinatal deaths, Poor technique of injection
prematurity, and toxemia of pregnancy was also higher in Allergen extract overdose
both control groups as compared to the SLIT group, but Manufacturer’s recommendation for dose reduction upon changing
within the expected incidence for the general population. to a new production
Another study, which retrospectively analyzed the safety of
SCIT in pregnancy, also concluded that that IT for allergic effects occur more frequently in patients during the
diseases is safe in pregnancy.[180] induction (up‑dosing) phase of treatment compared
to maintenance therapy.[188,189] SCIT‑related SRs can
All these studies show substantial evidence in favor range in severity from mild to life‑threatening or
of allergen IT; however, more studies are required fatal anaphylaxis. The incidence of SCIT SRs varies
involving long‑term clinical trials from the country. depending on the induction schedule, augmenting
factors, premedication, and the degree of sensitization.
Safety of Allergen Immunotherapy – In most surveys, the rate of SRs with nonaccelerated
A Global Perspective SCIT induction is approximately 0.1%–0.2% of injections
and 2%–5% of patients.[190,191]
The administration of allergens into an IgE‑sensitized
individual always implies a risk, however small, of Compared with SCIT, the SLIT‑related SR rate is
inducing local and systemic side effects.[3,99,169] LRs are significantly lower, and severe SRs are relatively
fairly common with both SCIT (erythema, pruritus, and uncommon. When introducing a new route of
swelling at the injection site) and SLIT (oropharyngeal administration, safety is a priority, especially when
pruritus, swelling, or both), affecting up to 82% of treatment is self‑administered at home.[95] Clinical trials
patients receiving SCIT[3] and 75% of patients receiving and pharmacosurveillance studies have demonstrated
SLIT.[181] Gastrointestinal symptoms associated with a very low rate of systemic adverse effects and no
SLIT can be classified as LRs (if only associated with life‑threatening systemic side effects with SLIT.[192,193] In
oral mucosal symptoms) or SRs (if occurring with other a comprehensive review of 104 SLIT studies published
systemic symptoms). LRs were “deemed not bothersome through October 2005, the SLIT‑related SR rate was 0.056%
at all or only slightly bothersome” by 82% of SCIT survey of doses administered (i.e. 14 probable SLIT‑related
respondents, with only 4% indicating that they would serious adverse events, which translated to 1.4 serious
stop SCIT because of the LR.[182] LRs are not predictive adverse events per 100,000 SLIT administered doses).[181]
of subsequent SRs with either AIT route.[183,184] No The Food and Drug Administration (FDA)‑approved
study found that increased frequency of large SCIT LRs product information of the three SLIT tablets includes a
increases the risk for future SRs.[185] warning about the possibility of severe allergic reactions
from SLIT and a recommendation that an epinephrine
Evidence suggests that the patients most likely to autoinjector be prescribed to patients receiving allergy
develop anaphylaxis are those who are highly sensitive tablets in the event a severe allergic reaction should
as determined by skin tests or sIgE tests, patients with occur. To date, there have been no confirmed reports
more severe disease (in particular with chronic and of SLIT‑related fatalities, but SRs of a severity to be
uncontrolled asthma)[186] and prior SCIT‑related SRs categorized as anaphylaxis have been reported.[194]
among others [Table 10].[187] It must be noticed that Unlike SCIT, the incidence of SRs does not appear
the occurrence of adverse events with SCIT largely to be related to induction schedule, allergen dose,
depends on the allergen type and preparation. Higher symptomatic asthma, or degree of sensitization. Because
frequency is seen with native allergens compared SLIT is administered in a setting without direct medical
to the hypoallergenic preparations and in animal supervision, specific patient instructions should be
dander compared to pollen and mite.[2] Systemic side provided regarding management of adverse reactions
and the clinical scenarios when the administration of contrast materials, hymenoptera stings, and certain
SLIT should be postponed (e.g., asthma exacerbation, foods (most notably, peanuts). Oral medications
acute gastroenteritis, and stomatitis or esophagitis). and many other types of exposures also have been
• SRs (anaphylaxis) are generally rare, but facilities implicated in anaphylaxis. Anaphylaxis may sometimes
for its management should be available at the place be idiopathic.
of skin testing and IT. SRs are categorized into
immediate SRs (occurring within 30 min) and late Anaphylactic reaction is clinically manifested by
SRs (debut >30 min after injection) respiratory distress, laryngeal edema, and/or intense
• Important symptoms of anaphylaxis include change bronchospasm, often followed by vascular collapse
in voice, frequent change in posture, itching in eye and or by shock without antecedent respiratory difficulty.
skin, redness in eye, appearance of symptoms – such Cutaneous manifestations exemplified by pruritus and
as rhinitis, asthma, and urticaria, fall in blood urticaria with or without angioedema are characteristic
pressure and feeble pulse, mental confusion, sinking of such systemic anaphylactic reactions. Gastrointestinal
sensation, and losing consciousness manifestations include nausea, vomiting, crampy
• Early signs of a severe reaction include a burning abdominal pain, and diarrhea.
sensation and pruritus of the palms and soles;
perianal or perigenital pruritus; an urge to defecate Adrenaline/epinephrine is the drug of choice for the
and urinate; sneezing attacks and generalized management of anaphylaxis.
pruritus. In addition, further respiratory and/or
cardiovascular symptoms may occur rapidly Prehospital interventions include high‑flow oxygen,
• Sequential increase in the size of swelling at the site cardiac monitoring, and facility for intravenous line.
of injection is suggestive of impending anaphylaxis Active airway intervention is needed in rare cases but
• Other complications may include vasovagal attack. may be difficult due to laryngeal or oropharyngeal
edema. Inhaled beta‑agonists are used to counteract
WAO SCIT SR grading system should be utilized to bronchospasm and should be administered to patients
identify SRs and grade them accordingly.[190] having wheezing. For large‑volume intravenous fluid
resuscitation, isotonic crystalloid solutions (i.e., normal
Anaphylaxis and its management saline, ringer lactate) are preferred. With mild
SRs (anaphylaxis) may occur in patients while skin testing cutaneous reactions, an antihistamine alone may be
with some antigens or initiation phase). Anaphylaxis sufficient. In patients with systemic manifestations
refers to severe allergic reaction, in which prominent of anaphylaxis, epinephrine is to be administered.
dermal and systemic signs including symptoms manifest. Patients taking β‑blockers may be resistant to the
The full‑blown syndrome includes urticaria (hives) and/ effects of epinephrine. Glucagon may be effective in
or angioedema with hypotension and bronchospasm. The this situation. Administration of corticosteroids is used
classic form, described in 1902, involved prior sensitization in anaphylaxis primarily to decrease the incidence and
to an allergen with later re‑exposure, producing severity of delayed or biphasic reactions. Corticosteroids
symptoms through an immunologic mechanism. An may not influence the acute course of the disease;
anaphylactoid reaction produces a very similar clinical therefore, they have a lower priority than epinephrine
syndrome but is not immune‑mediated. and antihistamines.
Pathophysiology of anaphylaxis is characterized by rapid Essential equipment/drugs (emergency kit) for the

onset of increased secretion from mucous membrane, treatment and monitoring of systemic anaphylactic
increased bronchial smooth muscle tone, decreased reactions[81] should be available, while skin testing and
vascular smooth muscle tone, and increased capillary injection (s) for AIT, as follows:
permeability after exposure to an inciting substance. • Stethoscope, blood pressure monitor
These effects are produced by the release of mediators, • Adrenaline (1 mg/ml) for injection
such as histamine, leukotriene C4, prostaglandin D2, • Antihistamine, corticosteroids, and vasopressor for
and tryptase. The release of these mediators are immune injection or oral treatment
mediated involving type I allergic reaction that occurs • Bronchodilator (rapidly acting β2 agonist for
when the antigen (allergen) binds to antigen‑sIgE inhalation or intravenous injection)
attached to previously sensitized basophils and mast • Syringes, needles, tourniquet, and equipment for
cells. The mediators are released almost immediately infusion
when the antigen binds. • Saline for infusion
• Oxygen (with face mask/nasal cannula) and suction
The most common inciting agents in anaphylaxis are equipment
parenteral antibiotics (especially penicillins), intravenous • Silicone mask and equipment for manual ventilation
• Forms for recording the course and treatment of to inhibition of the histamine‑converting enzyme
anaphylaxis. diamine oxidase[197]
• Antihistamine pretreatment during the initial phase
Precautions for systemic side effects of AIT has shown to reduce the frequency and
Before deciding the dose of allergen, a careful evaluation severity of systemic side effects.[198] In a controlled
of the patient suitability to receive the scheduled dose is trial of hymenoptera VIT involving a small number of
required to avoid systemic side effects. The precautions patients, antihistamine pretreatment was associated
recommended are as follows:[81,195] (1) IT should not be with a better clinical efficacy.[199] However, further
started during peak allergen season and (2) injections studies are required on this aspect. A potential
should not be administered when the patient has clinical problem is that the use of antihistamine pretreatment
symptoms or the symptoms should be controlled by may mask a mild reaction, which would otherwise
adequate medication. [92] As a safety precaution, a help in dose modification.
reduction in allergen dose during allergen season is
commonly recommended. Special Considerations
• AIT injections (SCIT) in patients with airway infection
or other significant diseases within the last 3 days can Monoallergen immunotherapy and mix allergen
be postponed immunotherapy
• Injections (SCIT) in patients with deterioration of One important variable in the administration of SCIT is the
allergy symptoms or increased need for anti‑allergic use of a single or multiple allergens. For example, allergy/
drugs due to recent allergen exposure within the last immunology specialists in the United States generally
3 days should be postponed administer mixtures of all of the major allergens (or a
• Injections (SCIT) should be postponed in patients representative of each group of allergens) to which the
with decreased lung function <80% of personal patient has been shown to be sensitive. In contrast, it is
best value. In asthmatic patients, measuring lung common in Europe to administer only the one or two
function before each injection is mandatory (peak allergens that appear to cause the most symptoms for that
flow measurement is sufficient) individual patient. Most of the studies in India have also
• The scheduled dose of antigen can be reduced if been on multiple allergen AIT. However, globally, most
the interval between injections has been exceeded. of the studies of SCIT efficacy used a single allergen, and
The magnitude of reduction depends on the degree thus, the efficacy of multiple allergen SCIT has not been
exceeded and should be defined in the clinical extensively evaluated in clinical studies.[187]
guidelines
• The scheduled allergen dose should be reduced in The prevalence of polysensitization has been
case of an SR at the preceding visit. The magnitude documented to increase with age, and a majority of
of reduction depends on the severity of the reaction the patients consulting an allergist are polysensitized.
and should be defined in the clinical guidelines. A polysensitized patient does not necessarily have
In case of anaphylactic and other life‑threatening polyallergy [Box 1 for their definitions].[200]
reactions, the continuation of SCIT should be carefully
evaluated (except in case of hymenoptera venom The management of patients with polysensitizations
allergy, in which it actually reinforces the indication and/or polyallergy has been dealt with in a recently
for IT) published review article. Understanding the
• Allergen injections (vaccine) should be administered sensitization and allergy profile of a patient can help the
separately from other vaccination for infectious allergist provide specific AIT with greater confidence.
diseases by at least a gap of 1 week In a patient with polysensitization, if the clinician
• Conventionally, the late LR at the injection site identifies only a single allergen responsible for the
is used to adjust the allergen dosage for the next most clinically relevant symptoms, then monoallergen
allergen administration. However, studies have IT with that allergen can be prescribed.[200]
indicated that the late LR at the preceding injection
is not related to a risk of developing an SR at the If two or more allergens are recognized as clinically
next injection[195] significant, then AIT may be initiated with parallel 2‑AIT
• Preinjection monitoring of patients also includes a (i.e., both allergens as individual AIT) or mixed 2‑AIT.
check of any drug intake that may either increase the The European Medicines Agency has recommended
risk of systemic side effects or render the treatment that allergists should mix nonrelated allergens as little
of anaphylactic reactions more difficult. Here, the as possible and should not mix seasonal and perennial
β‑blockers are the most important example.[196] Heavy allergens or allergens with proteolytic activity (such
drinking of beer may similarly increase risk due as extracts of HDMs, molds and insects) without
justification. Mixing allergens clearly has an impact on inflammation and remodeling in adolescents and young
pharmaceutical parameters (stability and dosing) and adults may increase the risk of asthma later in life.[203] As
clinical effects (optimal dose and safety). The authors of documented earlier, there is evidence that early‑specific
the review article also recommend that AIT with three or injection IT reduces the risk of asthma in children with
more allergen sources should only be considered in the allergic rhinoconjunctivitis[130] and diminishes the risk
very rare cases, in which all the allergens clearly cause of new sensitizations in monosensitized children.[118,119]
severe symptoms.[200]
Age limit for AIT in children:[8]
Understanding the principles of homologous groups • Age <2 years is an absolute contraindication for AIT
as suggested by Lorenz et al. can guide the clinician • Age 2–5 years is a relative contraindication for AIT
on the physicochemical and biological characteristics • Age ≥5 years can be prescribed AIT.
of allergen extracts that can help in defining the
strategy of monoallergen IT or mixing of allergens.[201] Quality Control of Allergen Extracts
Homologous groups have been suggested only for the
mites (Dermatophagoides species) and the pollen allergens. Several allergen vaccines (extracts) are available
D. pteronyssinus and D. farinae belong to the homologous commercially in the country. It is recommended
groups of HDMs. Among tree pollens, three groups have that allergen manufacturers should supply vaccines
been described – the birch group or Fagales group, group tested for consistency relative to an in‑house reference
of Oleaceae, and group of Cupressaceae. In grasses/cereals, standard. There has been significant progress in allergen
sweet grasses of the Poaceae (Gramineae) family, subfamily standardization in recent years, and a large number
of Pooideae have been identified as a homologous of standardized allergen extracts are marketed in the US
group. A group of weed pollen has also been described. and European countries. Indian researchers have also
Homologous groups have not been defined for insect published their work on biological standardization of
venoms, animal dander, and molds/fungi. pollen such as R. communis and Hydrangea integrifolia.[204]
Within a homologous group (such as Dermatophagoides In recent years, a lot of knowledge has been generated
species), the use of a single course of AIT with a mixture of in India on characterization of major/minor allergen
allergens that mimic natural exposure is recommended. of pollen, fungi, food, and insect sources. [34,51,205‑210]
Use of separate AIT formulations is preferable when However, the purified proteins (major allergens) and
treating with two nonhomologous allergens. monoclonal/polyclonal antibodies are not available for
characterization based on major allergen content. Under
When mixing two allergens from the homologous group, these circumstances, allergen extracts are standardized
the ratios between the individual allergen sources should based on weight/volume and protein estimation by
be the same. modified Lowry’s, bicinchoninic acid assay, or micro
Kjeldahl method. [211] Researches have shown that
Skin test and allergen immunotherapy during allergen source material processed by freeze drying
pregnancy gives better quality extracts.[207‑209] The pollen contents in
1. Do not perform skin testing in a pregnant woman the samples/raw materials should be >90% for grasses/
2. Do not start IT in a pregnant woman weeds and >95% in case of trees.
3. Skin testing and IT are to be avoided up to 6 months
after delivery or earlier if lactation is discontinued Most of the allergenic proteins (>80%) come in the
before solution within first few minutes of extraction. Recent
4. Do not discontinue IT if person is already on IT started studies have shown that 4–8 h extraction in PBS (pH 7.4)
much before pregnancy and receiving benefit from or ammonium bicarbonate (pH 8.0) yields extracts with
the therapy. optimum allergenic potency.[51,208,209] The extraction buffer
should contain phenyl methyl sulfonyl fluoride and
Allergen immunotherapy in children EDTA as protease inhibitors.
Compliance with the injection regimen may be affected
by age and may be problematic, particularly during the Fifty percent glycerol is a good stabilizer of proteins in
adolescent years. Children should accompany a parent, SPT solutions. However, same concentration cannot be
guardian, or other responsible person with them at each used for therapeutic extracts and the lower concentrations
visit. It is recommended to start IT at an early age in allergic are not effective.[212] Recently, sucrose or epsilon‑amino
children to modify the natural course of allergic disease. caproic acid (EACA) has been used successfully for
stabilizing grass pollen and cockroach extracts.[209,212] Cool
Airway remodeling may start early in life, especially gel packs or cold chain should be used/developed for
in children with severe asthma,[202] and ongoing airway transporting the extracts throughout the country.
Allergen extract(s) vary from one manufacturer to • Before initiating AIT, patients must be informed
another; hence, it is suggested that diagnostic and about the following: The practical procedure, type,
therapeutic allergen extracts should be procured from and duration of treatment; expected effects; as well
the same allergen manufacturer. as possible risks of and alternatives to treatment
• Most of the published randomized controlled
Drug controller of India/state unit(s) regulates the allergen studies of both SCIT and SLIT are conducted with
manufacture in the country. Currently, the emphasis is on single allergen extracts. These studies dominate the
good manufacture practice to be implemented in these meta‑analyses that indicate both SCIT and SLIT are
drug antigen units. However, the coordinated efforts of effective treatments for AR and allergic asthma. There
experts from ICAAI, Antigen Units and Drug Regulatory is conflicting evidence for the effectiveness of allergen
Authorities, are required to upgrade the quality control mixes.[213] The preparation of AIT with an increasing
of allergen extracts following standard WHO/IUIS/ number of extracts creates a potential for interactive
EMA protocols. In fact, there is need to develop allergen effects (cross‑reactivity, protease activity) that can
certification centers in the country such as FDA and change their allergenic and immunogenic properties.
Centre for Biologics Evaluation and Research in the USA Of particular importance is the contribution of
and Paul Ehrlich Institute in Europe. proteolytic enzymes in some fungal and whole‑body
insect allergenic extracts. For these reasons, the
The methods for antigen preparation and quality control number of allergens in an AIT prescription should
of extracts/vaccine are summarized below for reference: be limited to as low as possible, never more than 4
• Allergy units (AUs) recommended for defining • Recent evidence demonstrates that within a
potency of extracts vary across different countries. homologous group (such as Dermatophagoides
Hence, at present, weight/volume, protein species), the use of a single course of AIT with a
estimation (PNU in µg/ml), and SDS‑PAGE protein mixture of allergens that mimic natural exposure is
profile should be followed for maintaining the quality recommended. When mixing two allergens from the
of antigen in different batches homologous group, the ratios between the individual
• Source material for antigen extraction should be allergen sources should be the same (e.g., one should
freeze dried, fungal culture (extracts) of 10–20 days always use 1/2 of allergen source 1 and 1/2 of
should be taken, and PBS of 0.1 M, pH 7.2 has been allergen source 2 in a two‑allergen mixture, etc.).[200]
found most suitable for antigen extraction
• For stability of aqueous extracts, addition of sucrose However, in India, the pollen from different categories
or EACA is recommended may be mixed to reduce the number of injections and
• Allergen extracts should be free of contaminants to improve compliance. In such cases, the amount of
including of aflatoxins and endotoxins individual antigen should be decided depending on
• Sterility test is required for each batch of antigen their skin test positivity. The greater the positivity, more
extracts is the amount of that antigen to be included in vaccine.
• Storage of antigen: These allergens shall be mixed in proportion of skin
• The allergen extracts/vaccines should be stored sensitivity.[214] Such mixture of extracts may be diluted
at 2°C–8°C in a refrigerator 10 times or more to reduce the chances of an adverse event.
• In case of withdrawal of more antigen from the
vaccine vial, it should not be injected back in vial Several factors need to be considered when mixing
to avoid contamination allergens, including (1) cross‑reactivity, (2) optimal dose
• In case of electricity failure for more than 2 h, keep for each allergen, and (3) potential interaction between
vaccine in an ice box or any other cooling device/ different types of allergens (e.g., proteolytic enzymes).
pack • Allergens of the same group show cross‑reactivity;
• Transportation of antigen should be done using a hence, the most potent and relevant allergen should be
cooling container. selected from the group. If the relevance of the allergens
are equivalent, then mixing of allergens may be utilized
Standard Prescription (Protocol) for • Allergens to be mixed in AIT should be done with
Perennial Subcutaneous Immunotherapy precaution as certain allergens have proteolytic
enzymes and thus reduce the potency of other
• The allergens for AIT are decided after correlating with allergens. Hence, it is recommended not to mix
history, evidence of exposure to the allergen in the HDM or fungal or insect allergens with any other
patient environment, precipitation of symptoms after allergens and prescribe these preferably in separate
exposure, and skin test positivity preferably with an SPT vials. In India, practice of mixing all the allergens in
• In cases of rhinitis and sinusitis, it is important to single vials is done from last more than 50 years to
exclude mechanical causes such as gross DNS improve compliance and acceptability. The chances
Table 11: Standard dosing regimen for subcutaneous • AIT may be postponed if the patient is symptomatic
immunotherapy and presents with decreased lung function (i.e., <80%
Concentration Frequency Dose of the personal best value)
1:5000 Two injections in a 0.1-0.9 mL • Response to AIT starts slowly; however, clinical and
week (increments of 0.1 mL)
physiological improvement has been demonstrated
1:500 Two injections in a 0.1-0.9 mL
week (increments of 0.1 mL)
very shortly after the patient reaches a maintenance
1:50 One injection in a 0.1-0.5 mL
dose.[3] However, the time duration and efficacy are
week (increments of 0.1 mL) variable among individuals
1:50 One injection in 0.6 mL • If there is no clinical improvement observed after
2 weeks 1 year of therapy, the possible reasons for lack of
1:50 One injection in 0.7 mL efficacy with IT should be evaluated. The following
3 weeks reasons may be evaluated when there is no clinical
1:50 One injection in 0.8 mL improvement: (1) Failure to remove the causative
4 weeks
allergen exposure (e.g. animal dander), (2) exposure
1:50 One injection in 0.9 mL
4 weeks to high levels of allergen, (3) continued exposure
1:50 One injection in 1.0 mL to nonallergen triggers (e.g., tobacco smoke),
4 weeks (4) incomplete identification and treatment of
clinically relevant allergens, or (5) failure to treat with
Box 1: Definitions of polysensitization and polyallergy adequate doses of each allergen.
Polysensitization: Sensitization (according to standardized skin
prick tests or ssIgE assays) to two or more allergens If none of the above reasons are found, discontinuation
Polyallergy: Clinically confirmed allergy to two or more sensitizing of IT should be considered and other treatment options
allergens (i.e., causal relationships between exposure to two or more should be pursued.[3]
sensitizing allergens and clinical allergy symptoms) • In case of default – up to 1 month – no change in schedule;
1–2 months – continue with last lower dose; 2–4 months –
of misuse or overdose due to separate vials is a more continue with last dilution, and >4 months – restart AIT.
likely particularly for less illiterate patients This schedule has been advised as per the current Indian
• AIT should be prescribed only by the physician practice followed for over 50 years
trained in allergy and AIT and administered in his/ • Antigen for skin testing and for AIT should be
her presence in a place having facility of managing procured from the same manufacturer, to avoid
anaphylaxis difference in potency of the allergen. The difference
• AIT is started usually with 1:5000 w/v diluted antigen, in potency of extracts among different manufacturers
and the injections are given two times a week starting has been reported world over. Standardized
from 0.1 ml and increased in every injection by 0.1 ml. extracts should be used whenever available. Studies
• Use a tuberculin syringe with 26 number needle evaluating major allergens have documented their
• The injections are given subcutaneously presence in standardized allergens extracts
• If the dose is more than 0.5 mL – divide the • The allergen extracts produced for AIT can differ
injection in two sites in composition and allergen activity in two AIT
• The allergen vial should be kept in a refrigerator products.[5] Thus, data from one AIT product cannot
between 2°C and 8°C be extrapolated to other products even if they contain
• The schedule is as follows [Table 11] [detailed the same allergen sources.
dosing schedule is given in Appendix 1].
Future of Allergy Diagnosis and Allergen
The dosing regimen may be modified and patient can be Immunotherapy
initiated with a higher dilution in patients with higher
positivity on the SPT. Over the last 20 years, a large number of new diagnostic
• In cases showing high skin sensitivity or AIT with and therapeutic concepts have emerged in the field of
single antigen showing LR/SR at initiation of AIT, allergy management.
higher dilution, i.e., 1:50,000 w/v, can be selected and
the first injection should be given in the hospital/clinic Future of allergy diagnosis
• Usually, the maintenance dose is between 0.5 and In in vivo tests, one of the important future implications
1.0 ml of 1:50 dilution in different patients of allergy diagnosis includes availability and use of
• The duration is usually 3–5 years, but in India, standardized allergen extracts which can improve the
where it is not possible to avoid the presence of utility of allergy diagnosis. Preliminary studies have
antigens (mostly pollens, dust mites, and insects), also evaluated the in vivo component‑resolved diagnosis
the decision has to be individualized and have shown a promising approach.[215] Recombinant
allergens have also been used for SPT,[216] and skin tests research to improve IT. The future developments in
with recombinant and natural allergens have a similar value AIT would include newer routes of administration
if the recombinant allergens have been well selected and including intralymphatic IT (ILIT), epicutaneous (EPIT),
represent all or most epitopes of the natural allergen.[216,217] and intradermal AIT. In ILIT, allergen is given directly
in the lymph node with the aim for higher allergen
Provocation tests including nasal and conjunctival have amounts in secondary organs. ILIT requires much
been evaluated and recommended by International lower doses of allergen and fewer injections than the
organizations for the definitive diagnosis of IgE conventional SCIT modality, while maintaining the
sensitization and allergies. Specific NPT consists of same efficacy. EPIT has been tested with good results
controlled exposure to allergens and thereby eliciting a for both aeroallergens and food allergens. This route
response from the nasal mucosa in an allergic individual. currently seems particularly suitable in children[78] and
It is indicated for the diagnostic confirmation of allergic has a potential for self‑administration, safe, and needle
rhinitis and when discrepancies arise between medical free. The epicutaneous tissue has a number of antigen
history and the results of skin tests and/or serological presenting cells and is nonvascularized.
tests. It is also used to evaluate sensitivity to the
allergen, the efficacy and safety profile of treatment, In addition to the newer routes, newer formulations
and in research on the pathophysiological mechanisms (nanoparticles) are at early experimental stage, with
of nasal response to allergens. [218] Similarly, the positive results in animal models. Addition of adjuvants
conjunctival allergen provocation test reproduces the to allergen extracts is an additional possibility; crude
events occurring by instilling an allergen on the ocular allergen extracts can be improved by adding adjuvants,
surface. It is indicated especially when the relevance of which provide an additional enhancement of the TH1
the allergen is not obvious or in polysensitized patients response. An organic adjuvant usually stimulates the
suffering from IgE‑mediated ocular allergy.[219] Toll‑like receptors of the innate immunity, which in
turn favor the TH1‑oriented response. [223] Bacterial
Another area of interest is the development of molecular adjuvants are commercially available for SCIT globally
allergology for the diagnosis of allergic sensitizations. and have lower number of injections. DNA adjuvants
Development and progress made in the field of are under experimental investigation, with a single
recombinant allergens have allowed for the development human trial.[78]
of a new concept in allergy diagnosis, molecular
diagnosis, or component‑resolved diagnosis, which Peptide‑based IT is another future prospect. It is possible
makes it possible to identify potential disease‑eliciting to give only allergenic fragments, instead of the whole
molecules. This also presents as a new challenge for allergenic proteins, because antigen‑presenting cells
healthcare professionals for appropriate interpretation recognize linear sequences. Encouraging results from
of test results; clinicians must know about the basics clinical trial have been observed.[78,224] The recombinant
of allergen components, their clinical implications and allergens have been used to improve the IT by identifying
must always keep in mind that sensitization does not disease‑causing molecules. They have also been
necessarily imply a clinical allergy.[220,221] evaluated recently in clinical studies. However, their
overall efficacy has been similar to those provided by
The basophil‑activation test (BAT) measures basophil the crude extracts.[78] Further, pretreatment with anti‑IgE
response to allergen cross‑linking IgE. The clinical before AIT may reduce the systemic allergic reactions
impact of BAT is due to the unique ability of these cells in patients unable to reach the targeted maintenance
to degranulate on cross‑linking of the sIgE bound on dose for IT.
membrane‑bound high‑affinity IgE receptor (FcεRI) by
allergen exposure. Compared with the determination The future of AIT would also incorporate newer
of sIgE in serum, BAT reflects a functional response and upcoming indications ‑ food allergy, being the
as basophil activation can be induced by cross‑linking predominant one. A Cochrane review of egg allergy
of FcεRI, which requires more than binding of sIgE reviewed four RCTs with a total of 167 recruited
to allergen. The clinical applications of BAT range individuals (oral IT [OIT] 100; control 67 participants),
from diagnosis to monitoring the progress of AIT. all of whom were children (aged 4–15 years).[225] The
It a multifaceted and promising tool which needs to evidence suggested that OIT can desensitize a large
be further well established and evaluated in clinical number of egg allergic patients although it remains
practice.[222] unknown whether long‑term tolerance develops. In
addition, there are no standardized protocols for OIT
Future of allergen immunotherapy and the "data" remains experimental. Other important
Although AIT is specific, it is associated with some food allergens for which research is still ongoing include
side effects thereby newer treatments are under peanut and cow’s milk.[226]
Position Statements • AIT should be started at an early age as it has the

potential to modify the natural course of allergic
• AIT should be practiced only by allergy‑trained disease
doctors (physicians [MD], pediatricians, ENT • AIT can be continued in pregnancy but is usually not
surgeon, pulmonologists, dermatologists) and in a initiated in a pregnant woman
clinical setting where instruments and medications • Response to AIT starts slowly; however, clinical and
for the management of anaphylaxis are available physiological improvement has been demonstrated
• The treatment of allergic diseases is based on patient very shortly after the patient reaches a maintenance
education, allergen avoidance, pharmacotherapy, and dose. This should be explained to the patient
AIT • If there is no clinical improvement observed after
• SPT is the gold standard for the detection of allergen 1 year of therapy, the possible reasons for lack
sensitization of efficacy with IT should be evaluated. If no
• The treating physicians should be aware of local reasons are found, discontinuation of IT should be
and regional allergens prevailing in patient’s considered, and other treatment options should be
environment pursued
• AIT is indicated for the treatment of patients (≥5 years • The optimal duration of AIT is still debated. According
with no limit on the upper age) with allergic rhinitis/ to reports, AIT can be administered for 3–5 years in
conjunctivitis, allergic asthma, and allergic reaction patients with a good therapeutic response. However,
against insect sting/venom. AIT might have positive the decision to discontinue AIT after 5 years should
effects in selected sensitized patients with AD; the be based on individual patient basis
best evidence is available for HDM AIT • AIT for food is in the experimental stages and should
• Age <2 years is an absolute contraindication for AIT not be practiced until it has shown to have clinical
while the age of 2–5 years is a relative contraindication efficacy and safety
for AIT[8] • Studies suggest that VIT can be discontinued after
• AIT should be used in properly selected cases with 3–5 years in most of the patients. However, decision
a history of precipitation of attack after allergen to discontinue VIT should be taken on the response
exposure and positive SPT to clinically relevant of patient to treatment
allergens. The response of AIT is antigen‑specific • AIT is cost‑effective based on clinical response
administered to the patient. Unrelated/irrelevant with reduction in medicine requirements and
antigens based on skin text (sensitization) alone also persistence of benefit for 5–6 years after
should not be included in allergen vaccine discontinuation of IT
• Most of the randomized controlled studies of both • Skin testing as well as AIT can give severe
SCIT and SLIT are with single allergen extracts SR (anaphylaxis) at times. Therefore, skin testing and/
• Mixing of allergens (after looking at homologous or IT should be administered under the supervision
groups, dose, and compatibility) may be required of a trained physician who can recognize early
if the patient suffers from allergic disease due ≥2 symptoms and signs of anaphylaxis and administer
clinically relevant allergens requisite treatment in emergency unit
• When mixing two allergens from the homologous • Adrenaline is the drug of choice for IT‑induced SRs
group, the amount of the individual allergen extract • Allergens for diagnosis and AIT should be preferably
should be equal or select only most important allergen from the same manufacturer
based on highest skin positivity • Standardized allergen extracts should be used both
• When mixing allergens from the nonhomologous for allergy diagnosis and IT to obtain better response.
groups, the amount of individual antigen should Efforts are required to upgrade the standardization of
be decided depending on their skin test positivity. allergen extracts so that they can be defined in BUs, for
Compatibility of the allergens (cross‑reactivity and example, BAU, AUs, therapeutic unit, standardized
enzymatic degradation) should be remembered BUs. However, in India, following parameters are
before mixing allergens mandatory for manufacturers – protein content,
• Do not mix allergens with high proteolytic enzyme protein profile, and biopotency
activities (such as dust mites, fungal, and insects) with • Allergen extracts/vaccine (diagnostic/therapeutic
any other allergen and prescribe these preferably in antigen) should be stored at 2°C–8°C and transported
separate vials using cool device to maintain the allergenic potency.
• SCIT and SLIT both have clinical efficacy proven in
trials. However, SLIT is currently not approved in India Acknowledgments
• AIT is used in combination with pharmacotherapy We are thankful to all the core committee members,
to control the symptoms which would decrease with contributors for providing their valuable inputs in
the increasing efficacy of AIT framing the revised guidelines, 2017.
Financial support and sponsorship 15. Singh AB, Dahiya P. Pollen aerobiology and allergy: An integrated
approach. Indian J Aerobiology 1992;5:1‑19.
Nil.
16. Singh AB, Dahiya P. Allergens in India – We are different from
the West. In: Sheikh W, editor. Principles and Practice of Tropical
Conflicts of interest Allergy and Asthma. Mumbai: Vikash Medical Publishers; 2006.
There are no conflicts of interest. p. 61‑92.
17. Bisht V, Kukreja N, Singh BP, Arora N, Sridhara S. Current status
of fungal allergens. Indian J Allergy Asthma Immunol 2003;17:9‑19.
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Appendix
Appendix 1: Immunotherapy Dosing Chart (Vallabhai Patel Chest Institute, New Delhi)
Instructions:
1. Use tuberculin syringe, needle number 26
2. Give subcutaneous injections
3. After 0.5 mL, divide the injection in two sites
4. Keep the vial under refrigeration
5. Place next order before the last vials exhausts
Date Dose (mL) Severity and Doses and
frequency of frequency
Date Dose (mL) Severity Doses and asthma or of using
and frequency rhinitis steroids and/or
frequency of using bronchodilators
of asthma steroids and/or IV 1:50 (once in
or rhinitis bronchodilators 2 weeks – after III)
I 1:5000 (twice a week) 0.6
0.1 0.6
0.2 0.6
0.3 0.6
0.4 0.6
0.5 0.6
0.6 0.6
0.7 0.6
0.8 V 1:50 (once in
0.9 3 weeks – after IV)
II 1:500 (twice a 0.7
week – after I) 0.7
0.1 0.7
0.2 0.7
0.3 0.7
0.4 0.7
0.5 0.7
0.6 VI 1:50 (once in
0.7 4 weeks – after V)
0.8 0.8
0.9 0.8
III 1:50 (once a week – after 0.8
II) 0.8
0.1 0.8
0.2 0.8
0.3 VII 1:50 (once in
0.4 4 weeks – after VI)
0.5 0.9
0.5 0.9
0.5 0.9
0.5 0.9
0.5 0.9
0.5 0.9
0.5 VIII 1:50 (once in
0.5 4 weeks – after VII)
1.0
1.0
1.0
1.0
1.0
Maintenance dose with 1.0 mL of 1:50 should be continued once in 4 weeks
till discontinuation of allergen immunotherapy is considered
Algorithm for Allergy Management
Symptoms suggestive of
Allergic rhinitis/rhinoconjunctivitis and/or
Allergic asthma
Patient history and

clinical examination
Allergy diagnosis
(skin prick test [SPT])
Negative SPT Positive SPT
Positive Correlating with patient history &

patient history clinical symptoms
sIgE estimation Yes No
Avoidance of allergen Sensitization without

possible clinical relevance,
Negative Positive further diagnostic
work-up (if necessary)
No Yes
Observation of the course of
disease, differential diagnosis,
further diagnostic work-up
Incomplete Good
response response
? Suspected local allergy

Patient preference No Continue
for immunotherapy avoidance
Provocation test Negative
(Nasal/conjunctival) Yes
Positive
Allergen immunotherapy
Pharmacotherapy may be initiated following the initial visits and SPT (skin prick test)
AIT (allergen immunotherapy) should not be given only on the basis of serum specific IgE
Figure 1a: Algorithm for Allergy Management
Figure 1b: Algorithm for Allergy Management (contd.)

Guidelines For Practice of Allergen Immunotherapy in India: 2017-An Update

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Introduction allergic rhinitis/rhinoconjunctivitis. AIT

Gaur, et al.: Guidelines: Practice of AIT in India - 2017 update

Gaur, et al.: Guidelines: Practice of AIT in India - 2017 update

Figure 1: Mechanism of AIT

Table 2: Contraindications for allergen A document on aeroallergens (pollens) in different

Gaur, et al.: Guidelines: Practice of AIT in India - 2017 update

Gaur, et al.: Guidelines: Practice of AIT in India - 2017 update

Gaur, et al.: Guidelines: Practice of AIT in India - 2017 update

Gaur, et al.: Guidelines: Practice of AIT in India - 2017 update

Subcutaneous Immunotherapy Rush immunotherapy

Gaur, et al.: Guidelines: Practice of AIT in India - 2017 update

Gaur, et al.: Guidelines: Practice of AIT in India - 2017 update

Gaur, et al.: Guidelines: Practice of AIT in India - 2017 update

Gaur, et al.: Guidelines: Practice of AIT in India - 2017 update

Gaur, et al.: Guidelines: Practice of AIT in India - 2017 update

Gaur, et al.: Guidelines: Practice of AIT in India - 2017 update

Table 9: Systematic reviews comparing subcutaneous and sublingual immunotherapy

The safety of VIT is related to the nature of the venom

Gaur, et al.: Guidelines: Practice of AIT in India - 2017 update

Gaur, et al.: Guidelines: Practice of AIT in India - 2017 update

Gaur, et al.: Guidelines: Practice of AIT in India - 2017 update

Pathophysiology of anaphylaxis is characterized by rapid Essential equipment/drugs (emergency kit) for the

Gaur, et al.: Guidelines: Practice of AIT in India - 2017 update

Gaur, et al.: Guidelines: Practice of AIT in India - 2017 update

Gaur, et al.: Guidelines: Practice of AIT in India - 2017 update

Gaur, et al.: Guidelines: Practice of AIT in India - 2017 update

Gaur, et al.: Guidelines: Practice of AIT in India - 2017 update

Gaur, et al.: Guidelines: Practice of AIT in India - 2017 update

Position Statements • AIT should be started at an early age as it has the

Gaur, et al.: Guidelines: Practice of AIT in India - 2017 update

Gaur, et al.: Guidelines: Practice of AIT in India - 2017 update

Gaur, et al.: Guidelines: Practice of AIT in India - 2017 update

Gaur, et al.: Guidelines: Practice of AIT in India - 2017 update

Allergy 2006;61:855‑9. Clin Immunol 2006;118:434‑40.

Gaur, et al.: Guidelines: Practice of AIT in India - 2017 update

Gaur, et al.: Guidelines: Practice of AIT in India - 2017 update

Gaur, et al.: Guidelines: Practice of AIT in India - 2017 update

Gaur, et al.: Guidelines: Practice of AIT in India - 2017 update

Algorithm for Allergy Management

Patient history and

Negative SPT Positive SPT

Positive Correlating with patient history &

sIgE estimation Yes No

Avoidance of allergen Sensitization without

? Suspected local allergy

Figure 1a: Algorithm for Allergy Management

Gaur, et al.: Guidelines: Practice of AIT in India - 2017 update

Figure 1b: Algorithm for Allergy Management (contd.)

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