Who benefits?
Multiple randomized, prospective, placebo
controlled studies [3] have demonstrated the effectiveness of IT in the
treatment of allergic rhinitis and allergic asthma. There must be a clear
temporal relationship between exposure to the allergen and symptoms. The
indications for allergen IT include clinically significant disease, in terms of
duration and severity. Examples of severe symptoms include inability to sleep
due to symptoms or interference with work or school performance. Patients may
have perennial symptoms or severe symptoms during a specific season. Other
indications include unresponsiveness to therapy (allergen avoidance and/or
medication) or unacceptable adverse effects of pharmacotherapy.
Special consideration should be given to patients
with asthma. IT should not be initiated in patients with poorly controlled
asthma symptoms, as it has been demonstrated that deaths from IT are more common
in symptomatic subjects with asthma. Therefore, patients receiving IT injections
should be asymptomatic and have a forced expiratory volume in 1 second (FEV1) of
at least 70% of predicted.[4]
What's in the shot?
Allergen extracts are commercially available for
common aeroallergens, such as pollens (trees, grass, and weeds), molds/fungi,
dust mites, cats, and dogs. Some allergen extracts are standardized, such as cat
hair, house dust mites (Dermatophagoides pteronyssinus and
Dermatophagoides farinae), short ragweed, and timothy grass. Most,
however, are not standardized and therefore can vary widely in biologic activity
and potency.
Knowledge of local and regional aerobiology, as
well as allergen cross-reactivity, is important in the selection of allergens.
Diagnostic allergy skin testing is performed with these allergenic extracts,
which are then used to prepare IT treatment sets.
Immediate hypersensitivity skin testing is
generally the preferred method of testing for specific IgE antibodies (sIgE). IT
should be considered when positive test results for sIgE correlate with
suspected triggers and patient exposure. IT should not be given to patients with
negative test results or those with positive test results that fail to correlate
with suspected triggers, clinical symptoms, or exposure.
For example, your patient, a teenager who lives in
Chicago,
complains of sneezing, rhinitis, and ocular pruritus every August and September.
Skin testing is performed, which reveals sensitization only to trees. In this
patient, IT would not be clinically indicated. It would be expected that if skin
test findings were clinically relevant, symptoms would predominate in the spring
during tree pollen season. This patient's symptoms are more consistent with
ragweed sensitization. Therefore, IT is not indicated in this patient as he
fails to report springtime symptoms. He has a non-allergic component to his
rhinitis, which may be treated with pharmacotherapy.
How does it work?
The immunologic changes associated with
immunotherapy are complex and the mechanisms have not been fully elucidated.
What we do know is that IT reduces the immediate phase response of an allergic
reaction, specifically by inducing a reduction in release of mediators, such as
histamine, from basophils and mast cells. IT has also been shown to block the
late-phase allergic response.
Successful immunotherapy is associated with a
change from a Th2 toward a Th1 CD4+ cytokine profile. Increased production of
IL-12, a strong inducer of Th1 responses, is implicated in contributing to this
shift. IT is also associated with immunologic tolerance, which can be defined by
the generation of CD4+CD25+ regulatory T lymphocytes producing IL-10, TGF-beta, or
both. Efficacy from IT is not dependent on reduction in allergenspecific IgE
levels. Therefore, one cannot rely on in vitro (RASTs or ImmunoCAPs) or
in vivo (skin prick) test results to monitor response to therapy.
Efficacy is established based on the level of clinical improvement
observed.
Where should it be administered?
The IT injections are administered subcutaneously
in the posterior portion of the middle third of the upper arm. Injections should
be administered under the supervision of an appropriately trained physician. The
preferred location for administration of IT is in the office of the physician
who prepared the patient's allergen IT extract (ie, the allergist's office), but
this is not always practical or convenient for families. Regardless, the
injection should be given in a physician-supervised setting where emergency
equipment and medications (namely epinephrine) are readily available. Home
administration is inadvisable due to the risk of anaphylaxis. There is also
increased risk of systemic reactions when patients transfer physicians,
particularly when the extract is changed. Therefore, it is generally recommended
that patients plan to remain with the same physician during the duration of the
treatment.
How often are the shots given?
There are 2 phases of allergen immunotherapy
administration: (1) the build-up phase, which is when the dose and concentration
of allergen extract are slowly increased, and (2) the maintenance phase, which
is when the therapeutic dose is delivered. During the build-up phase, if
injections are given 1-2 times per week, maintenance can be reached within 4-6
months. During maintenance, an interval of every 2-4 weeks is recommended for at
least 3-5 years. Dose adjustments must be made for missed or late injections and
for systemic reactions.
What are the risks?
The prevalence of severe systemic reactions is
less than 1% of patients receiving IT on a conventional schedule. Risk factors
for severe IT reactions include symptomatic asthma and administration during the
peak pollen season. Previous systemic reactions to IT injections may be another
contributing factor.
Aeroallergen IT is not generally recommended in
patients using beta-blockers (and possibly angiotensin converting enzyme
inhibitors) due to potential difficulties in treating systemic reactions. These
medications may attenuate the patients' response to epinephrine.
Patients should wait at least 30 minutes after the
immunotherapy injection(s) so that reactions can be recognized and treated
promptly if they occur. The majority of severe reactions develop within 30
minutes after the IT injection. Patients at increased risk of a systemic
reaction may need to stay in the physician's office for more than 30 minutes
after the injection.
Systemic reactions must be treated with
epinephrine intramuscularly. The IT dose and schedule, and whether IT should be
continued, should be evaluated after such a reaction. Patients at high risk of
reaction should also be advised to carry autoinjectable epinephrine in case
symptoms begin to develop after the patients' departure from the physician's
office.
In contrast to systemic reactions, local reactions
are fairly common and can be managed with local treatment (cool compresses or
topical steroids) and antihistamines. Generally, local reactions are poor
predictors for subsequent systemic reaction and dose reductions for most local
reactions are not necessary. However, a retrospective review5 found that the
rate of large local reactions (25 mm wheal) was 4 times higher among patients
who experienced systemic reactions. This suggests that individuals with a higher
frequency of large local reactions may be at greater risk for systemic
reaction.
Why should it be given to children?
IT has been shown to be effective and often well
tolerated in children. Specifically, studies [3] have demonstrated the
following:
1. Improvement in symptom control for asthma and
allergic rhinitis
2. Decreased risk of development of
asthma
3. Decreased development of new sensitivities to
additional aeroallergens
Efficacy is generally gauged by subjective
measurements by the patient. Decrease in symptoms or amount of medication
required to control symptoms are generally noted within a year of starting
treatment (on maintenance therapy). Several studies have demonstrated
significant improvement in standardized quality of life measures.
Children under 5 years of age may have difficulty
cooperating with IT. The injections, particularly due to the frequency required,
can be traumatic to young children. These patients may also have more difficulty
communicating the symptoms of a systemic reaction. The risks and benefits must
be weighed in each individual case.
What about venom immunotherapy (VIT)?
IT is also indicated for stinging insect
hypersensitivity or Hymenoptera allergy.[6] Hymenoptera venoms include honeybee,
yellow jacket, wasp, hornet, and fire ant. Fire ants are found primarily in the
southeast United
States. Anaphylactic sting reactions account
for at least 40 US deaths per year. VIT is recommended in all patients who have
experienced a systemic reaction to an insect sting who can demonstrate sIgE to
venom allergens. VIT lowers the risk of systemic reaction to stings for up to 20
years after treatment has been stopped.[7] These benefits appear to be greater
in children than in adults.[7]
However, VIT is not indicated in children 16 years of age
who have experienced cutaneous systemic reactions (without any respiratory or
cardiovascular manifestations). This includes children 16 years of age
and younger who have flushing, hives, or swelling (not affecting mucus membranes such
as oral mucosa) in an area on the skin not contiguous with the site of
the sting. Prospective studies have shown that children 16 years of age or younger
have approximately a 10% chance of having a systemic reaction if re-stung and if
a systemic reaction does occur, it is likely to be limited to the
skin.
Therefore, the risks of VIT in these patients
generally outweigh the benefits. Patients, however, may be prescribed
autoinjectable epinephrine and be counseled about ways to prevent stings.
Examples include keeping food covered until eaten, wearing closed-toe shoes
outdoors, and not wearing brightly colored clothing or perfume when
outdoors.
VIT is certainly indicated in any child who
develops symptoms that are laryngeal (stridor, hoarseness, throat clearing),
respiratory (wheezing, coughing, shortness of breath), and/or cardiovascular
(syncope, loss of consciousness) after a sting.
What's on the horizon?
Sublingual immunotherapy (SLIT) is under clinical
investigation in the United
States. In this route of administration, high
doses of allergen extract are placed under the tongue and subsequently
swallowed. The advantage of SLIT is that it appears to be associated with a
lower incidence of side effects than injection therapy. The decrease in
potential risk also applies to younger children, under 5 years of age. Moreover,
given the safety profile, this route of administration would not require
delivery in a medically supervised setting and hence may be acceptable to a
greater number of patients. At this time, SLIT has not been approved for
clinical use by the US Food and Drug Administration.
REFERENCES
[1.] Moller C,
Dreborg S, Ferdousi HA, et al. Pollen immunotherapy reduces the development of
asthma in children with seasonal rhinoconjunctivitis (the PAT-Study). J Allergy
Clin Immunol 2002;109:251-256.
[2.] Jacobsen
L, Niggemann B, Dreborg S, et al. Specific immunotherapy has long-term
preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT
study. Allergy 2007;62:943-948.
[3.] Cox L, Li
JT, Nelson H, Lockey R, eds. Allergy immunotherapy: A practice parameter, second
update. J Allergy Clin Immunol
2007;120:S25-S85.
[4.] Bosquet J,
Hejjaoui A, Chivert H, et al. Immunotherapy with a standardized
Dermatophagoides pteronyssinus extract. III. Systemic reactions during the
rush protocol in patients suffering from asthma. J Allergy Clin Immunol
1989;83:797-802.
[5.] Roy SR,
Sigmon JR. Olivier J, et al. Increased frequency of large local reactions in
patients who experience systemic reactions on allergen immunotherapy.
Ann Allergy Asthma Immunol
2007;99:82-86.
[6.] Moffit JE,
Golden DBK, Reisman RE, et al, eds. Stinging insect hypersensitivity: A Practice
Parameter Update. J Allergy Clin Immunol
2004;114:869-886.
[7.] Golden
DBK, Kagey-Sobotka A, Norman, PS, et al. Outcomes of allergy to insect stings in
children, with and without venom immunotherapy. N Engl J Med
2004;351;668-674. | 
