Compliance with the provisions in this LCD may be monitored and addressed
through post payment data analysis and subsequent medical review audits.  
  
 **History/Background and/or General Information**  
  
Allergen Immunotherapy is defined as the repeated administration of specific
allergens to individuals with IgE-mediated conditions to provide protection
against allergic symptoms and inflammatory reactions associated with natural
exposure to these allergens.1  
  
Allergen immunotherapy should be considered for patients who have discernable
evidence of specific IgE antibodies to clinically relevant allergens. The
decision to begin allergen immunotherapy may depend on a number of factors,
including but not limited to, patient's preference/acceptability, adherence,
medication requirements, response to avoidance methods, and the adverse
effects of medications. The severity and duration of symptoms should also be
considered when evaluating the need for allergen immunotherapy.1  
  
The presence of IgE antibodies alone does not infer the need for
immunotherapy; the presence of IgE antibodies to an allergen must correlate
with the patient's history.1 For example, the presence of IgE antibodies to an
allergen not locally found, with no history of exposure or expectation of
exposure, would not be considered clinically relevant.  
  
In order for allergen immunotherapy to be considered medically reasonable and
necessary **both** of the following criteria must be met:

  1. The allergen(s) to which the patient is allergic must be clinically relevant, and
  2. Trial of avoidance measures has failed or there is unavoidable exposure to allergy triggers identified in allergy testing.1

**Covered Indications**  
  
Conditions for which immunotherapy will be considered medically reasonable and
necessary include:

  1. Allergic rhinitis
  2. Allergic conjunctivitis
  3. Allergic asthma2-9
  4. Dust mite atopic dermatitis1,9-11
  5. Stinging insect hypersensitivity (e.g., bees, hornets, wasps, fire ants)1-9

  
Although all treatment regimens must be individualized for a given patient,
immunotherapy generally has two phases. A **build-up phase** and a
**maintenance phase**.  
  
The **build-up phase** includes the initiation and subsequent increase of
applicable antigen concentrations within 8-28 weeks. Usually a single dose
increase is administered per visit and visits generally vary from 1-3 times
per week. Accelerated timetables, also referred to as rush or cluster
immunotherapy, involve giving several injections at increasing doses on a
single visit.1,9  
  
The **maintenance phase** occurs when the effective therapeutic dose is
reached. This dose provides therapeutic effectiveness without significant
adverse local or systemic consequences. This dose may not be the initial
targeted concentration/dose. The maintenance immunotherapy schedule is
generally every 4-8 weeks for venoms and every 2-4 weeks for inhalant
allergens. Maintenance immunotherapy generally involves follow-up visits every
6-12 months.1,2,9  
  
 **Length of Maintenance Therapy:** The duration of all forms of immunotherapy
must be individualized. A presumption of failure can be made when, after 12-24
months of therapy, a person does not experience:

  1. A noticeable decrease of symptoms,
  2. An increase in tolerance to the offending allergen, and
  3. A reduction in medication usage.  
  

For many patients, the recommended duration of allergen immunotherapy is 3-5
years. However, the duration of immunotherapy should be individualized based
on the benefits sustained from therapy, disease severity, immunotherapy
reaction, patient preference and certain antigens in the therapy.1,2,9  
  
 **Desensitization** is the rapid administration of incremental doses of
allergens or medications by which effector cells are rendered less reactive or
nonreactive to an IgE-mediated immune response. Tolerance to medications can
be achieved through desensitization.1  
  
**Limitations  
**

  1. Patients should not have substantial comorbid conditions that could increase immunotherapy risk (e.g., severe asthma uncontrolled by pharmacotherapy, significant cardiovascular disease).
  2. Patients on beta-blockers and/or angiotensin-converting enzyme (ACE) inhibitor medications must have individualized assessments of risk versus benefit prior to receiving inhalant or venom allergen immunotherapy.
  3. Patients should be able to cooperate during therapy.
  4. Please refer to the CMS IOM Publication 100-02, _Medicare Benefit Policy Manual,_ Chapter 15, Section 50.4.4.1 Antigens for additional limitations.
  5. Please refer to the CMS IOM Publication 100-03, _Medicare National Coverage Determinations (NCD)_ _Manual_ , Chapter 1, Part 2 Sections 110.9 Antigens Prepared for Sublingual Administration and 110.11 Food Allergy Testing and Treatment for additional limitations.

  
**_Allergen immunotherapy is not considered medically reasonable and necessary
for_** :

    1. Food hypersensitivity1,12-14
    2. Cockroach hypersensitivity1
    3. Urticaria and/or angioedema1,12,13
    4. Provocation-neutralization therapy
    5. Low-dose subcutaneous therapy based on the Rinkel method6,12,13
    6. Therapy formulations, such as allergoids or adjuvants1
    7. The following routes of administration6,12,13:
      * Oral or sublingual for food immunotherapy
      * Epicutaneous immunotherapy
      * Intralymphatic immunotherapy
      * Intranasal immunotherapy
      * Sublingual Immunotherapy
    8. Immunotherapy for Hymenoptera venom sensitivity using whole-body extracts, with the exception of fire ant extracts.1,2,9
    9. Multiallergen subcutaneous immunotherapy1

  
**Place of Services (POS)  
  
** Immunotherapy may have severe unpredictable systemic and local reactions
within the first 30 minutes following the injection. It is recommended that
immunotherapy be administered in a setting that permits the prompt recognition
and management of adverse reactions, particularly anaphylaxis. It is
recommended that patients wait at the physician's office/medical clinic for at
least 30 minutes after the immunotherapy injection.1,6,9  
  
Home administration of allergen immunotherapy should only be considered in
rare and exceptional cases when the benefits of immunotherapy clearly outweigh
the risks. Frequent or routine home immunotherapy is not considered
appropriate under any circumstances. If this method is utilized, informed
consent should be attained from the patient and the individual administering
the injection must be trained and equipped to recognize and manage
immunotherapy reactions, particularly anaphylaxis.1

**Provider Qualifications  
 _  
_**Services will be considered medically reasonable and necessary when all
aspects of care are within the scope of practice of the provider's
professional licensure; and when all procedures are performed by appropriately
trained providers in the appropriate setting.  
  
 **Notice:** Services performed for any given diagnosis must meet all of the
indications and limitations stated in this LCD, the general requirements for
medical necessity as stated in CMS payment policy manuals, any and all
existing CMS national coverage determinations, and all Medicare payment rules.

A literature search was conducted using the following key words: allergens;
allergen immunotherapy; practice guidelines; practice parameters; meta-
analysis; systematic review; allergic rhinitis; seasonal allergic rhinitis;
allergic conjunctivitis; allergic asthma; inhalant allergies; routes of
immunotherapy administration; subcutaneous immunotherapy; allergen-specific
immunotherapy, atopic dermatitis; acute and chronic urticaria; skin rash; food
allergies; stinging insect allergy; Hymenoptera; anaphylaxis.  
  
 **Evidence-Based Guidelines  
  
** A Joint Task Force represented by the American Academy of Allergy, Asthma &
Immunology (AAAAI); the American College of Allergy, Asthma & Immunology
(ACAAI); and the Joint Council of Allergy, Asthma & Immunology (JCAAI) has
provided an updated practice parameter for allergen immunotherapy.1 Also, the
European Academy of Allergy and Clinical Immunology (EAACI) and the AAAAI
provided an updated, comprehensive consensus report which includes the
mechanisms of allergy immunotherapy and its use in clinical practice.6 In
addition, the AAAAI and the ACAAI have provided a practice parameter update
for stinging insect hypersensitivity.2  
  
Allergen immunotherapy is defined as the repeated administration of specific
allergens to individuals with IgE-mediated conditions to provide protection
against allergic symptoms and inflammatory reactions associated with natural
exposure to these allergens. Immunotherapy is effective for pollen, animal
allergens, dust mites, mold/fungi, and Hymenoptera hypersensitivity. Allergen
immunotherapy should be considered for patients who have discernable evidence
of specific IgE antibodies to these allergens.1  
  
The decision to begin allergen immunotherapy may depend on a number of
factors, including but not limited to, patient's preference/acceptability,
adherence, medication requirements, response to avoidance methods, and the
adverse effects of medications. The severity and duration of symptoms should
also be considered when evaluating the need for allergen immunotherapy.
Patient assessments should include a detailed clinical history, an applicable
physical evaluation, and particular laboratory tests. Allergy testing results
provide a conclusive diagnosis (e.g., immediate hypersensitivity skin tests,
in vitro tests for serum specific IgE). When tests outcomes are positive for
select IgE antibodies that align with likely triggers and patient exposure,
immunotherapy is recommended; however, the manifestation of specific IgE
antibodies alone does not infer the need for immunotherapy; the presence of
IgE antibodies to an allergen must correlate with the patient's history.1  
  
Many well-designed controlled trials show that allergen immunotherapy is
effective for individuals with symptoms of allergic rhinitis/conjunctivitis,
allergic asthma and stinging insect hypersensitivity.2-9 Also, randomized
trials demonstrate that allergen immunotherapy inhibits the development of
asthma in individuals with allergic rhinitis.15 Several studies have also
shown that aeroallergen immunotherapy may be beneficial for individuals with
atopic dermatitis resulting from aeroallergen sensitization to dust
mites.1,9-11  
  
Venom immunotherapy (VIT) is recommended for individuals with a history of a
systemic reaction to Hymenoptera stings who demonstrate Hymenoptera-specific
IgE antibodies and exhibit large local reactions (LLRs). In this regard,
measurements of serum tryptase levels are recommended in individuals with a
history of moderate to severe anaphylactic reactions to stings. Studies have
shown that greater serum tryptase levels are correlated with recurrent and
severe systemic responses (including deadly reactions) to VIT injections,
increased failure rates in VIT, and increased relapse rates with
discontinuation of VIT. While venom extracts are available for honeybees,
yellow jackets, white-faced hornets, yellow hornets, and wasps, there is
currently no venom extract available for fire ants. However, literature
supports the use of whole-body extract (WBE) to be used as a reagent for
diagnostic testing and immunotherapy for fire ant sting allergy.1,2,9  
  
The provider prescribing immunotherapy should be trained and experienced in
prescribing and administering immunotherapy. The prescribing provider must
choose the applicable allergen extracts based on the patient's medical
history, allergen exposure history, and the presence of specific IgE
antibodies. The prescription must indicate the initial dose, the target
maintenance dose, and the immunotherapy schedule.1,2  
  
Immunotherapy treatments are generally separated into two phases; the build-up
phase and the maintenance phase. The build-up phase (also referred to as
updosing, induction, or dose-increase) involves gradually giving greater doses
within 8-28 weeks. Usually a single dose increase is administered per visit
and visits generally vary from 1-3 times per week. Accelerated timetables,
also referred to as rush or cluster immunotherapy, involve giving several
injections at increasing doses on a single visit. While accelerated timetables
provide a means of reaching the therapeutic dose sooner, a greater risk of a
systemic reaction is possible in some individuals.1,9  
  
The maintenance phase occurs when the effective therapeutic dose is reached.
This dose provides therapeutic efficiency without significant adverse local or
systemic consequences. This dose may not be the initial targeted
concentration/dose. The maintenance immunotherapy schedule is generally every
4-8 weeks for venoms and every 2-4 weeks for inhalant allergens. Maintenance
immunotherapy generally involves follow-up visits every 6-12 months. If
clinical improvement is not achieved after 1 year of maintenance
immunotherapy, potential reasons for lack of effectiveness should be
investigated and if no reasons are discovered, cessation of immunotherapy
should be contemplated and other therapy possibilities should be explored. For
many patients, the recommended duration of immunotherapy is 3-5 years.
However, the duration of immunotherapy should be personalized based on the
benefits sustained from therapy, disease severity, immunotherapy reaction,
patient preference, and certain antigens in the therapy.1,2,9  
  
Generally, the initial dose is 1,000 to 10,000-fold less than the maintenance
dose. The maintenance dose is usually 500-2,000 allergy units (AU) (e.g., for
dust mites) or 1,000-4,000 bioequivalent allergy units (BAU) (e.g., for grass
or cat) for standardized allergen extracts. For non-standardized extracts, a
recommended dose is 3,000-5,000 protein nitrogen units (PNU) or 0.5 mL of a
1:100 or 1:200 weight/volume dilution of manufacturer's extract. If the main
allergen concentration for the extract is available, a maintenance dose of
5-20 micrograms (g) of the major allergen is recommended for inhalant
allergens and 100 g for Hymenoptera venoms.1,2  
  
 __Desensitization involves the rapid administration of incremental doses of
allergens or medications by which effector cells are rendered less reactive or
nonreactive to an IgE-mediated immune response. Desensitization can involve
IgE-mediated or other immune mechanisms. A positive skin test response to the
allergens might lessen or actually convert to a negative response in some
situations after desensitization. Tolerance to medications can be achieved
through desensitization.  
  
Immunotherapy may have severe unpredictable systemic and local reactions
within the first 30 minutes following the injection. It is recommended that
immunotherapy be administered in a setting that permits the prompt recognition
and management of adverse reactions.6 The preferred location for such
administration is the prescribing physician's office. However, patients can
receive immunotherapy at another health care facility if the physician and
staff at that location are trained and equipped to recognize and manage
immunotherapy reactions, particularly anaphylaxis. It is recommended that
patients wait at the physician's office/medical clinic for at least 30 minutes
after the immunotherapy injection. Regardless of the location, allergen
immunotherapy should be administered under the direct supervision of an
appropriately trained physician, qualified nurse practitioner or physician
assistant in a facility with the proper equipment, medications, and personnel
to treat anaphylaxis.1,9  
  
The risk of severe systemic reactions is low with allergen immunotherapy that
is administered appropriately; however, life-threatening and fatal reactions
do happen. Studies have shown that severe responses following allergen
immunotherapy occur in less than 1% of patients receiving conventional
immunotherapy, but occur in about 34% of patients receiving rush (e.g.,
accelerated timetable) immunotherapy.1



**Limitations for Immunotherapy**

Immunotherapy injections should be withheld if the patient presents with an
acute asthma exacerbation; allergen immunotherapy should not be initiated
unless the patient's asthma is stable with pharmacotherapy as patients with
severe or uncontrolled asthma are at a greater risk for systemic reactions to
immunotherapy injections. Regarding inhalant and venom allergen immunotherapy,
individual evaluations of risk versus benefit must be made for individuals on
beta-blockers and angiotensin-converting enzyme (ACE) inhibitor
medications.1,2,9  
  
Home administration of allergen immunotherapy should only be considered in
rare and exceptional cases when the benefits of immunotherapy clearly outweigh
the risks. Frequent or routine home immunotherapy is not considered
appropriate under any circumstances. If this method is utilized, informed
consent should be attained from the patient and the individual administering
the injection must be trained and equipped to recognize and manage
immunotherapy reactions, particularly anaphylaxis.1



**Methods of Immunotherapy not Supported in the Literature**

In addition to the subcutaneous route, allergen extracts can be given by
various methods. However, there are currently no FDA-approved formulations for
a non-injection immunotherapy extract. In this regard, the quality of evidence
in the literature does not support the following methods of immunotherapy:
Oral and sublingual immunotherapy (SLIT) for food hypersensitivity,
multiallergen subcutaneous immunotherapy (SCIT), neutralization-provocation
therapy, low-dose subcutaneous therapy based on the Rinkel method, intranasal,
intra-bronchial, intralymphatic, and epicutaneous. Further research is needed
to clarify the utility and efficacy of these methods.1,6,12,13

**Conditions not Supported in the Literature for Immunotherapy**

The quality of evidence in the literature is lacking in support of allergen
immunotherapy for food hypersensitivity, cockroach hypersensitivity, chronic
urticaria and/or angioedema, and therefore, is not recommended.1,12,13 The use
of therapy formulations, such as allergoids and adjuvants is also not
supported in the literature.1

Allergen immunotherapy, also known as allergy shots involves the repeated
administration of allergen extracts to individuals with IgE-mediated
conditions to decrease symptoms and improve quality of life during subsequent
natural allergen exposure. Allergen immunotherapy consists of administering
increasingly greater doses of specific allergens to individuals who have shown
immunologic sensitivity or reaction to a particular allergen through allergy
testing.  
  
Multiple evidence-based practice guidelines and appropriate use criteria are
available for allergen immunotherapy. Many well-designed controlled studies
have shown that immunotherapy is effective for pollen, animal allergens, dust
mites, mold/fungi, and Hymenoptera hypersensitivity. Also, aeroallergen
immunotherapy is recommended for individuals with atopic dermatitis resulting
from aeroallergen sensitization to dust mites. In addition, venom
immunotherapy (VIT) is recommended for individuals with a history of a
systemic reaction to Hymenoptera stings who demonstrate Hymenoptera-specific
IgE antibodies and exhibit large local reactions (LLRs). Measurements of serum
tryptase levels are also recommended for these individuals as increased serum
tryptase levels are correlated with recurrent and severe systemic responses
(including deadly reactions) to VIT injections, increased failure rates in
VIT, and increased relapse rates with discontinuation of VIT. Also, the use of
whole-body extract (WBE) is recommended for fire ant sting allergy as venom
extracts are not currently available for fire ants.  
  
The decision to begin allergen immunotherapy may depend on a number of
factors, including but not limited to, patient's preference/acceptability,
adherence, medication requirements, response to avoidance methods, and the
adverse effects of medications. The severity and duration of symptoms should
also be considered when evaluating the need for allergen immunotherapy.
Patient assessments should include a detailed clinical history, an applicable
physical evaluation, and particular laboratory tests. Evidence-based
guidelines recommend immunotherapy when allergy testing results are positive
for select IgE antibodies that align with likely triggers and patient
exposure. The presence of IgE antibodies alone does not infer the need for
immunotherapy; the presence of IgE antibodies to an allergen must correlate
with the patient's history.  
  
Per evidence-based guidelines, the provider prescribing immunotherapy should
be trained and experienced in prescribing and administering immunotherapy. The
prescribing provider must choose the applicable allergen extracts based on the
patient's medical history, allergen exposure history, and the presence of
specific IgE antibodies. The prescription must indicate the initial dose, the
target maintenance dose, and the immunotherapy schedule.  
  
Evidence-based guidelines recommend that immunotherapy be administered in a
setting that permits the prompt recognition and management of adverse
reaction. The preferred location for such administration is the prescribing
physician's office. However, patients can receive immunotherapy at another
health care facility if the physician and staff at that location are trained
and equipped to recognize and manage immunotherapy reactions, particularly
anaphylaxis. It is recommended that patients wait at the physician's
office/medical clinic for at least 30 minutes after the immunotherapy
injection as immunotherapy may have severe unpredictable systemic and local
reactions within the first 30 minutes following the injection. Regardless of
the location, allergen immunotherapy should be administered under the direct
supervision of an appropriately trained physician, qualified nurse
practitioner or physician assistant in a facility with the proper equipment,
medications, and personnel to treat anaphylaxis.  
  
Evidence-based guidelines support the following limitations for allergen
immunotherapy: 1) Patients should not have substantial comorbid conditions
that could increase immunotherapy risk (e.g., severe asthma uncontrolled by
pharmacotherapy, significant cardiovascular disease); 2) Patients on beta-
blockers and/or angiotensin-converting enzyme (ACE) inhibitor medications must
have individualized assessments of risk versus benefit prior to receiving
inhalant or venom allergen immunotherapy; 3) Patients should be able to
cooperate during therapy; and 4) Home administration of allergen immunotherapy
should only be considered in rare and exceptional cases when the benefits of
immunotherapy clearly outweigh the risks. Frequent or routine home
immunotherapy is not considered appropriate under any circumstances.  
  
The quality of evidence in the literature does not support the following
methods of immunotherapy: 1) oral and sublingual immunotherapy (SLIT) for food
hypersensitivity; 2) multiallergen subcutaneous immunotherapy (SCIT); 3)
neutralization-provocation therapy; 4) low-dose subcutaneous therapy based on
the Rinkel method; 5) intranasal; 6) intra-bronchial; 7) intralymphatic; and
8) epicutaneous. Further research is needed to clarify the utility and
efficacy of these methods. Also, the quality of evidence in the literature is
lacking in support of allergen immunotherapy for the following conditions: a)
food hypersensitivity; b) cockroach hypersensitivity; and c) chronic urticaria
and/or angioedema. In addition, the use of therapy formulations, such as
allergoids and adjuvants is also not supported in the literature.