Allergen Immunotherapy

Efren Rael, MD

KEYWORDS
 Allergy immunotherapy  Standard subcutaneous immunotherapy (SCIT)
 Food immunotherapy  Venom immunotherapy (VIT)  Aeroallergen

KEY POINTS
 Allergies affect a large proportion of the population.
 Allergies can adversely affect productivity, sleep, and quality of life and can lead to life-
threatening reactions.
 Allergies can spread to affect multiple organ systems.
 Allergen immunotherapy (AIT) is the only therapy that can change the natural history of
allergic disease.

INTRODUCTION

Allergies in general affect a large percentage of the global population. There is wide
variability in methods reporting allergic rhinitis prevalence, ranging from 8.4% of
children and 7.7% of adults affected in the United States1,2 to up to 40% affected
worldwide.3 Asthma affects 18.7 million American adults or 8% of the adult population
and 6.8 million children or 9.3% of the pediatric population2 and affects 20% of the
European population.4 Skin allergy affects 12.5% of the United States population
under 18 years of age5 and 15% of the European population.4
Food allergy prevalence and food-triggered anaphylaxis have increased over the
past 2 decades as reported in a study comparing 2011 to 2012 with 2004 to 2005,
in age groups 0 to 4 years and 5 to 14 years,6 with additional studies supporting these
findings.79 The Centers for Disease Control/National Center for Health Statistics
report 5% prevalence of food allergy in individuals under 18 years of age.5 Indirect
and direct costs associated with food allergy in children and adolescents are large.
Management of pediatric food allergy increased total household costs in a European
cohort by V3961 in children and V4792 in adolescents.10
Life-threatening stinging insect allergy affects 0.4% to 0.8% of children and 3% of
adults.11 Stinging insect allergy accounts for greater than 10% of anaphylaxis cases.12
AIT is the only therapy that can change the underlying natural history of the allergic
conditions discussed previously and has been around for more than 100 years in
various forms to treat allergy.13,14 Pharmacologic therapies and allergen avoidance

Sean N. Parker Center for Allergy and Asthma Research, Stanford University, Box 18885, Stanford,
CA 94309, USA
E-mail address: efrenrael@gmail.com

Prim Care Clin Office Pract 43 (2016) 487494

http://dx.doi.org/10.1016/j.pop.2016.04.004 primarycare.theclinics.com
0095-4543/16/$ see front matter 2016 Elsevier Inc. All rights reserved.
488 Rael

measures can temporarily decrease symptoms; however, once discontinuation of

these measures occurs, the immune system often reverts back to the allergic state.

DIAGNOSIS
 History
 Allergy testing
 Outside of food allergy, allergen challenge is usually not performed to confirm the
diagnosis.
 Food challenge is confirmatory for the diagnosis of food allergy but should be
done by a specialist with hospital support in the event anaphylaxis management
is required.
The history is imperative to the diagnosis of allergic disease. Allergy history often
consists of a sensitization phase, whereby the immune system establishes recognition
of an allergen, followed in time by an effector phase, by which the immune system can
respond to an allergen challenge and memory is established.15
Allergies often lead to a history of itch, mucus production, and swelling on allergen
challenge. Allergies commonly affect the exposure site in a sensitized individual.
For example, inhaled allergens can affect the upper and/or lower respiratory systems
on allergen challenge16 and can elicit symptoms of sneezing, itchy nose, rhinorrhea,
and nasal congestion in the upper respiratory tract. In an asthmatic, symptoms
can include cough, wheeze, shortness of breath, and chest tightness on allergen
challenge.
Beyond allergic reaction development at the interface exposure site (such as the
skin, eyes, and respiratory mucosa), once memory is established, if an allergen is
able to get past a body barrier interface, circulating IgE allergic antibodies in the
bloodstream can be a catalyst for more advanced systemic reactions. Allergens can
bypass the natural barrier interface through capillaries under the tongue, absorption
from the gastrointestinal tract, or injection from a stinging insect (such as a honey
bee, wasp, hornet, yellow jacket, or fire ant). Food allergens, stinging insect venom
allergens, and, less commonly asthma, can lead to life-threatening allergic reactions.
Once the history is suggestive, testing can help identify the allergen to which an in-
dividual is sensitized. Testing can be accomplished via a skin test or a blood test. For
inhaled allergens and venom allergy diagnosis, allergen challenge is not usually
required. In the setting of food allergy, however, some foods have components that
are cross-reactive with environmental pollens and can elicit minor symptoms, such
as mouth itch, thereby making it difficult to determine if there is true food allergy or
a bystander effect from shared pollen allergen epitopes. As a result, food allergy
skin and blood tests are not reliably accurate to confirm a diagnosis of food allergy,
and indiscriminant food allergy testing without an allergy history can lead to unneces-
sary food avoidance, psychological angst for families, and, in severe cases, nutritional
deficiencies. Hence, a food challenge to the suspected food associated with allergy
symptoms is the gold standard for diagnosing food allergy. Food challenges should
be conducted in a hospital setting by an expert in the field, in the event that emergent
management with autoinjectable epinephrine and fluid resuscitation is required.

TYPES OF IMMUNOTHERAPY
 Aeroallergen, stinging insect venom, food
 Food immunotherapy is evolving.
 Standard and rush immunotherapy protocols
 Allergen Immunotherapy 489

AIT has been around for more than 100 years to treat symptoms associated with inhaled
allergens.13,14 Treatments typically involve escalating doses of the allergen of concern
over time, with goals of inducing tolerance to the allergen. Guideline-based approaches
are available for treatment of aeroallergens and stinging insect venom allergy.11,17 Venom
and aero-AIT treatment was initially pioneered by subcutaneous treatment.
Standard subcutaneous immunotherapy (SCIT) treatment options to environmental
pollens and stinging insect venom typically consist of serial escalations in allergen
dose, starting with very dilute concentrations of the allergen, often on a weekly basis, un-
til maintenance (an undiluted dose) is achieved, whereby treatments are resumed often
on a monthly basis. Rush and cluster immunotherapy protocols exist with expedited
schedules to reach maintenance.18 It is unclear whether rush or cluster aeroallergy
immunotherapy SCIT protocols carry a risk of provoking more anaphylactic reactions
and an increased need for systemic corticosteroid use. Accelerated protocols in venom
immunotherapy (VIT) do not seem associated with an increased anaphylaxis risk.11
In the United States, sublingual immunotherapy (SLIT) has recently been Food
and Drug Administration approved for grass (Grastek [Merck, Whitehouse Station,
NJ] and Oralair [Stallergenes S.A., Antony, France]) and ragweed (Ragwitek [Merck,
Whitehouse Station, NJ]), with more options undergoing clinical trials. In Europe and
Australia, sublingual therapy has been used for many years.
Food immunotherapy treatment options are evolving, with multiple studies currently
being conducted to demonstrate safety and efficacy. Food allergy treatment modal-
ities currently under investigation include Viaskin (DBV Technologies, Bagneux,
France), a food allergy patch, and CODIT (Aimmune, Brisbane, CA), an oral immuno-
therapy food capsule to food(s) with or without omalizumab. SCIT is not approved in
food allergy treatment due to an increased risk of anaphylaxis.

PROGNOSIS
 Generally good, but carries a small risk of anaphylaxis
 Allergen immunotherapy requires a compliant and motivated patient
 Treatment of underlying comorbid conditions helps improve response.
 Allergy symptoms usually worsen without treatment.
Studies demonstrate immunotherapy provides benefit for allergic rhinitis, allergic
asthma, eczema, and stinging insect venom allergy, with emerging data suggesting
benefit for food allergy.11,17,1921 Immunotherapy benefits tend to improve with time
on treatment. Multiple studies have identified that aero-AIT prevents asthma,22,23
minimizes symptoms associated with allergen exposure, improves quality of life, and
has the potential for beneficial effects on sleep, which may improve productivity at
school and/or work.17,2427 Additionally, immunotherapy can prevent life-threatening
allergic reactions to stinging insects11 and emerging data are accumulating to suggest
the same with food immunotherapy.19 Despite this, compliance is often poor.2831
A German national health insurance beneficiaries database with a cohort of 118,754
patients demonstrated that among the 2431 (2%) patients treated with immuno-
therapy in 2006, observed over a 5-year period from 2007 to 2012, and compared
with the cohort who did not receive AIT over the same time, AIT was associated
with a lower incidence of asthma (relative risk, 0.60; 95% CI, 0.420.84).23
Variability in response patterns tends to relate to duration of treatment and optimal
allergen dosing. Support should be given to increase compliance, with advice to pa-
tients on potential side effects and management, assessment of patient motivation,
and communication on a regular basis to review treatment response and side effects
and to address any fears/concerns associated with treatment.
490 Rael

AIT should be continued for a minimum of 3 years. Studies suggest no additional

benefit for treatment beyond 5 years.32 Individuals with severe systemic allergic re-
actions to venom might still be in danger on resting, despite 5 years of treatment,
and require indefinite VIT treatment.11 National databases on patient compliance
suggest completion of 3 years of AIT is challenging. In a German national database
comprising 85,241 patients receiving SCIT to pollen or dust mites and 706 patients
receiving pollen SLIT, compliance for 3 years was low, but higher in perennial SCIT
at 60% versus 27% for preseasonally administered SCIT; with an overall prescrip-
tion fill of 42% combined for pollen and 45% combined percent for mites. SLIT
compliance was lowest, with 16% of patients completing 3 years of therapy.28
A Dutch database of 6486 patients, comprising 2796 SCIT-treated and 3690
SLIT-treated patients, demonstrated 18% of the entire group reached 3 years of
therapy, of which 23% were SCIT treated and 7% were SLIT treated, respec-
tively.29 Median SCIT duration was 1.7 years duration and SLIT was 0.6 years
duration.29 Studies suggest SLIT compliance success rates are dependent on pa-
tient personal motivation.33
For subjects who do complete treatment, SCIT is demonstrated efficacious for
birch, mountain cedar, grass, ragweed, Parietaria, dog, cat, molds Cladosporium
and Alternaria, cockroach, and house dust mites.17,3436 Benefits include improved
quality of life and decreased medication requirements. Both SLIT and SCIT are cost
effective versus pharmacologic management.34,3739
In a Cochrane meta-analysis assessing SLIT asthma, there was not enough
evidence to prove efficacy in asthma.40 Most studies, however, assessed subjects
with mild or intermittent asthma and most studies lacked outcome data from validated
asthma symptom/quality-of-life questionnaires and medication scores.
Food oral immunotherapy studies suggest benefit. Oral immunotherapy looks
promising in peanut, milk, and egg.41 Food SLIT and food patch studies also look
promising.41,42

CLINICAL MANAGEMENT
 Concurrent comorbid condition management (both allergic and nonallergic) is
important during immunotherapy treatment.
 Asthma should be stable during immunotherapy.
 Patient selection is important.
 Immunotherapy is safe in pregnancy, but dose escalation should not be
performed.
AIT improves atopic eczema, allergic rhinitis, allergic asthma, and stinging insect
venom allergy. Evidence is increasing for food allergy immunotherapy benefits as well.
The rate of symptom improvement while on immunotherapy can be highly variable,
likely due to patient comorbid conditions, patient age, geographic environmental ex-
posures, genetic variability, and compliance.43 During immunotherapy treatment, con-
current management of comorbid conditions should be implemented per published
guidelines. Specifically, comorbid conditions, such as obesity, second-hand tobacco
smoke/pollution exposure, and review of patient specific factors, such as gender, age,
diet, exercise, and number of allergen triggers (as a correlate to severity), may have an
impact on treatment response patterns and outcomes.4447 In general, 3 years of
immunotherapy have been identified as an important milestone for benefit persistence
beyond completion of therapy. More than 5 years of immunotherapy is not thought to
provide additional benefit, with the exception of severe venom-allergic individuals,
who may require indefinite VIT.11
 Allergen Immunotherapy 491

AIT is safe in pregnancy and can be continued at the level achieved on becoming
pregnant.17 Up-dosing should not be performed during pregnancy because increases
in immunotherapy dosing can carry the risk of anaphylaxis. Ideally, pregnancy is
achieved while on maintenance immunotherapy or initiated in the postpartum period.
Contraindications to immunotherapy include noncompliance, unstable asthma, signif-
icant cardiovascular disease posing a risk to resuscitation, and anaphylaxis treatment
with epinephrine. b-Blocker use is a relative contraindication to immunotherapy due to
the potential to negate epinephrine anaphylaxis treatment. VIT treatment failure risk
factors include honeybee VIT-induced systemic allergic reaction, mastocytosis, and
angiotensin-converting enzyme use.48

DISEASE COMPLICATIONS
 Safe when performed by an allergy/immunology specialist
 Unstable asthma is a major risk factor.
 Anaphylaxis and eosinophilic esophagitis in food immunotherapy
Local reactions to immunotherapy are common and include itch, swelling and pain at
the treatment site. Local reactions can be treated with supportive care, including ice
packs in the first 48 hours to decrease swelling, pretreatment/cotreatment with antihis-
tamines, and heat packs after 48 hours. Systemic reactions to immunotherapy are rare
but can be fatal.17 Hence, the physician administering immunotherapy should discuss
the risks and benefits of treatment with patients and provide information on warning
signs associated with anaphylaxis. This information should be documented in a patients
medical record and informed consent should be obtained. A majority of systemic reac-
tions to immunotherapy occur within the first 30 minutes after treatment. Hence, patients
should be monitored for 30 minutes after treatment and personnel trained in anaphylaxis
management and resuscitation should be present during the observation period.
SLIT is approved for home use. Grass SLIT (Grastek) is approved in ages 5 to 65.
Ragwitek is approved for ages 18 to 65. The first dose is administered in a physicians
office with a 30-minute observation period, 12 weeks before the expected start of the
respective allergy season and continued for up to 3 years. Patients should be pre-
scribed an autoinjectable epinephrine at the time of treatment. Severe or uncontrolled
asthma, a history of eosinophilic esophagitis, and history of anaphylaxis to SLIT are
contraindications to treatment. Oralair, an allergy SLIT tablet, is approved for ages
10 to 65 and comes in 2 doses. Treatment should be initiated 16 weeks before the ex-
pected start of grass season and given coseasonally for up to 3 years. The first dose is
given in the clinic and subsequent doses are given at home.
Food immunotherapy is in different stages of investigation and treatment modalities.
Oral immunotherapy carries the risk of anaphylaxis. Hence, clinical trials evaluating
this therapy prescribe autoinjectable epinephrine to subjects undergoing food allergy
immunotherapy. In addition to anaphylaxis, potential side effects include emesis, aspi-
ration, abdominal pain, nausea, diarrhea, respiratory symptoms, cardiovascular
symptoms, throat swelling, respiratory symptoms, and skin symptoms. It is unclear
if eosinophilic esophagitis is a rare potential side effect of food oral immunotherapy,
and many clinical trials are screening for this condition prior to, during, and after
food immunotherapy trials.49

SUMMARY

AIT is a safe, cost-effective method for treating many allergic conditions. AIT may be
lifesaving in VIT and in food allergy and AIT can prevent the development and/or
492 Rael

progression of asthma. Comorbid diseases, such as obesity, gender, age, and trig-
gers, likely alter immunotherapy response patterns. Patient selection is important. In
an era trending toward precision medicine, AIT provides a unique opportunity to
personalize medical care.44

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