ARTICLE
Definition
Specific hyposensitization (also called specific immunotherapy) is a
method of causal treatment of allergic diseases and is defined as "repeated
application of increasing doses of the relevant allergen until reaching
loss of symptoms or a maintenance dose" [1, 2].
It has been in clinical use since 1911, when Noon and Freeman first
treated patients with pollinosis by injecting pollen allergens [3, 4].
During recent decades there has been considerable progress regarding
allergen extracts, modifications and general understanding. Still, there
are many problems and questions, which will be discussed shortly.
Mechanism of action
The precise mechanism of action of hyposensitization is not completely
understood [2]. Among many hypotheses the switch from Th 2- into Th
1 reaction pattern in the T cell regulation has gained wide acceptance
[5]. Some hypotheses of the mechanism of specific hyposensitization are
shown in Table I.
Efficacy
The efficacy of specific hyposensitization has been assessed in controlled
studies [2], which have to fulfill the following criteria:
double-blind, placebo-controlled, randomized;
patients selected according to well-defined clinical criteria
and allergy diagnosis;
exactly defined and standardized allergen extracts, if possible,
the extract should contain all the active proteins and not only major
allergens;
an optimal maintenance dose, this is the dose of allergen which
induces a high clinical effect without causing unacceptable side effects;
sufficient duration of treatment (there is no consensus); the
efficacy of treatment increases with the duration of therapy, so the minimum
treatment should be 3 years; treatment can be stopped after significant
improvement and negative results in prick tests.
Allergen extract (vaccine)
An allergen extract is obtained by extraction of the active ingredients
of animal or vegetable substances with a suitable menstruum. European
and American societies of allergology recommend [6], that all allergen
vaccines should be standardized for total allergenic potency, biological
activity, and major allergen measurements in mass units. Vaccines for
which standardization is not feasible, or those which do not state the
total potency and concentration of individual allergens should not be
used.
A confusing problem in determining total allergenic potency is standardization,
with many different and arbitrary units in use (e.g. W/V-, Noon-PNU
= Protein Nitrogen Unit, AU = allergy unit, BU = Bioequivalent allergy
Unit, IU = international Unit).
Allergen extracts for hyposensitization are either unmodified (aqueous)
or modified chemically, and/or by adsorption to different carriers (Table
II).
Aqueous allergen vaccines can be used for both venom and aero allergen
hyposensitization. The allergen is liberated quickly, which increases
the risk of side effects, occurring mostly within 30 minutes of injection.
The interval of injections is 3 to 5 days and many injections are necessary
to reach the maintenance dose. Because of the quick allergen liberation,
side effects can be more easily estimated and controlled.
In the semi-depot extracts, the allergen is adsorbed to substances delaying
its liberation. Therefore injection intervals can be extended up to 2
weeks. Allergen extracts can be modified by extraction with pyridine and
absorption to aluminumhydroxide or calcium phosphate. Aluminium salts
can induce subcutaneous nodules, which normally disappear after therapy.
The depot effect can be increased by adsorption to tyrosine.
Allergoids are chemically modified and have more immunological effects
and less side effects than aqueous, unmodified vaccines. There is more
experience with formaldehyde and glutaraldehyde modified vaccines than
with methoxypolyethylenglycol modified extracts or alginate modified vaccines.
The depot effect can be increased by additional adsorption to aluminium
or tyrosine.
Toxicity of allergen extracts, even of venom vaccines, is not a problem.
Honey bee venom, e.g. will be lethal only after more than several
hundred stings [7].
The vials containing the vaccines have to be labeled with important
patients' data and additional extracts' data, including a designation
of relevant units, shelf-life, therapeutic dosage schedules, and appropriate
methods for storage.
Mixtures of allergen extracts
In the case of multiple sensitizations, vaccines containing mixtures
of these can be prescribed. It must be taken into consideration that dilution
by multiple allergens will result in suboptimal doses of individual allergens
and the potency of an allergen may deteriorate more rapidly when diluted
or mixed with other allergen vaccines [8]. Allergen extracts should therefore
be distributed as either vaccines from a single source material or mixtures
of related, cross-reacting allergen vaccines.
Indications
Indications for specific hyposensitization are IgE-mediated allergic
diseases such as allergic rhino-conjunctivitis, allergic asthma and hymenoptera
venom allergy.
Before starting treatment, additional indoor allergens must be reduced
(e.g. removing of pets, eradication of dust mites), otherwise hyposensitization
leads to an allergen overload, which can induce severe allergic reactions.
Hyposensitization of allergic asthma and of perennial or seasonal allergic
rhinitis with pollen or dust mite extracts showed good results [9-12].
Considering that 25% of the patients with allergic rhinitis develop allergic
asthma within 10 years, a hyposensitization therapy should be initiated
in the early stages of the disease.
Some allergologists consider atopic eczema as a contraindication for
hyposensitization, others report on evident improvement of the eczema
[13]. A placebo controlled and double blind hyposensitization of monozygotic
twins with severe atopic eczema and exacerbation during the pollen season
showed a surprising result. From the second treatment year on, eczema
improved significantly in the girl who was treated with venum [14]. Patients
with atopic eczema should in any case be followed carefully and treated
with low doses.
Theoretically, patients with "oral allergy syndrome", caused by related
antigens from pollen and certain fruits and vegetables, or other pollen-associated
food allergies, can expect an improvement after hyposensitization with
the corresponding pollen allergen. But further clinical studies are still
required.
Hyposensitization therapies with molds and animal hair are the subject
of controversy among allergologists. Hitherto, due to poor standardization,
mold extracts repeatedly gave problems. New standardized extracts of Chladosporium
and Alternaria spp. seem to be promising [15, 16]. Hyposensitization with
animal hair is controversial, considering that allergen contact can be
avoided easily. Although some studies document improvement of allergic
asthma after hyposensitization with cat hair extracts [17], this treatment
should be reserved for people with occupational contact with animals (e.g.
animal keepers, veterinarians, circus artists).
The indication for hyposensitization in insect venom allergy results
from the combination of patient history, systemic symptoms of anaphylaxy
and proof of IgE-mediated sensitization (positive skin test, positive
RAST, positive in vitro mediated release).
The hyposensitization therapy with highly purified insect venoms is
highly effective, with success rates of about 90% [18]. The effectiveness
of wasp venom is higher than that of bee venom. But even a successful
hyposensitization does not spare the patient the need to carry an emergency
kit.
The indication for hyposensitization with hymenoptera venoms requires
a systemic anaphylactic reaction plus evidence of an IgE-mediated sensitization
(skinprick test and/or RAST). A high risk of increased exposure alone
(e.g. bee keepers) is not an indication for hyposensitization.
There is no age limit for hyposensitization with hymenoptera venoms
[19]. Rhinoconjunctivitis or asthma are typical diseases of children and
young people and mostly disappear during midlife. The onset of inhalant
allergies in older people is rare but may also present an indication for
hyposensitization.
Hyposensitization in children follows the same considerations for diagnosis
and treatment as for adults. Starting treatment during the early phase
of the disease may modify the allergic disease and prevent the progression
from allergic rhinitis to asthma and is thought to be more effective than
hyposensitization in adults. Severe allergic reactions to hymenoptera
venom in childhood are rare but they occur [20, 21].
The major problems of hyposensitization in children are the compliance
and the difficulty of controlling severe side effects. These problems
are more severe, the younger the children are [22].
According to most authors hyposensitization should not be started in
children under the age of 5, except for children with life-threatening
anaphylaxis to hymenoptera venom. Parents must give their permission for
the therapy and the children must be accompanied by adults.
Contraindications
Hyposensitization therapy should not be started
or continued in cases of [6]:
acute or chronic infections;
severe asthma uncontrolled by pharmacotherapy and/or irreversible
airway obstruction (e.g. pulmonary emphysema) (except for hymenoptera
venom hypersensitivity);
significant cardiovascular diseases which increase the risk of
side effects from epinephrine (except for hymenoptera venom hypersensitivity);
autoimmune disease;
immundeficiency disease;
malignancy;
severe psychological disorders;
medication with ß-receptor blockers;
medication with ACE-inhibitors;
poor compliance;
children under 5 years of age (except hymenoptera venom hypersensitivity).
Pregnancy and convulsions are no longer considered to be contraindications.
Studies with children with cerebral convulsions showed no changes in EEG
after the injection of allergen. In cases of pregnancy during hyposensitization
therapy, there is no need to discontinue the injections if they were well
tolerated previously. Possibly the maternal IgG production may prevent
an atopic disease in the new-born. However, the initiation of a hyposensitization
therapy should be postponed until the child is born.
Routes of hyposensitization
Parenteral allergen injection is the principal approach in hyposensitization.
However, the inconvenience and discomfort of frequent injections and their
risk of adverse reactions led to the investigation of other routes of
allergen application:
It has been shown, that the local application of allergens stimulates
the local immune system and has a systemic effect. It is self-administered
and the patient must be instructed to follow the physician's administration
schedule carefully and to attend regular follow-up consultations.
In oral application the vaccine (prepared as tablets, drops or capsules)
is either immediately swallowed or held in the mouth sublingually for
2 minutes before swallowing. In nasal and bronchial application the vaccine
(aqueous or prepared as powder) is delivered in the nose or into the bronchi
respectively [23].
Oral hyposensitization is the subject of controversy. In some studies
efficacy was described [24], but it was less than with parenteral hyposensitization.
It can be tried, especially in highly sensitized patients or children
[18]. Nasal or bronchial hyposensitization, especially with powdered allergens,
can induce bronchospasm and this makes the usefulness of immunotherapy
questionable.
Oral (OIT) and sublingual (SLIT) immunotherapy differ with regard to
pharmacokinetics. While a complex processing of antigens is likely to
occur in the stomach and gut after the preparation is swallowed, a prompt
and rapid absorption is expected with the sublingual route [25].
Passive hyposensitization with gamma-globulines requires further clinical
evaluation.
Side effects and risks
There is a broad variety of possible side effects in hyposensitization,
ranging from harmless local reactions to lethal anaphylactic reactions:
local reaction;
deterioration of an atopic disease;
type-III-reaction (immune-complex-disease);
unspecific symptoms;
anaphylaxis.
Shortly after injection, in most of the patients, erythema, swelling,
pain or pruritus can be observed. Although harmless, the reactions can
be so uncomfortable for the individual that the dose must be adjusted.
Infections at the injection site must be prevented by prior skin disinfection
and instruction to the patient that he should not scratch the itching
reaction. Especially after the injection of aluminium-containing allergen
preparations, some patients develop subcutaneous nodules, which usually
disappear after the end of the treatment. Rarely, pseudolymphoma can occur
[26].
During hyposensitization atopic symptoms of diseases like rhinitis,
asthma or atopic eczema may be triggered or worsened.
Several reports indicate the possibility of induction of immune complexes
during hyposensitization like serum sickness [27] with arthralgia, fever,
urticaria and nephritis or doubtful relations to polyarteriitis nodosa
[28] and allergic vasculitis [29]. These symptoms suggest that the maintenance
dose is too high and indicate the possibility that excess amounts of IgG
induced circulating immune complexes.
The most dangerous side effect of hyposensitization is systemic anaphylaxis.
The prevalence of these reactions ranges between 4 and 15% of patients
with aeroallergens, with variations between different extracts [30, 31]:
Skin: pruritus, flush, urticaria, angioederma.
Abdomen: nausea, cramping, defecation, diarrhea.
Respiratory tract: rhinorrhea, hoarseness, dispnea, laryngeal
edema, bronchospasm, cyanosis, respiratory arrest.
Cardiovascular system: arrhythmia, shock, cardia arrest.
The frequency of systemic reactions with insect venoms is a little higher.
Most reactions occur with higher doses. The critical dose lies between
1 and 10 µg, and at the maintenance of 100 µg, 30% of the patients
develop more or less severe systemic reactions at least once during hyposensitization
[22]. Systemic reactions usually occur within the first 30 minutes of
injection, but can also be found on rare occasions after several hours.
Death after hyposensitization has been described. Frankland [32] estimates
one death in 750,000 injections. The American Academy of Allergy, Asthma
and Immunology reports on 46 hyposensitization related deaths in the years
between 1945 and 1989 [33]. Frequent risk factors of these patients were
seasonal asthma, a high degree of hypersensitivity, or medication with
ß-receptor blockers. A consequent report on the years 1985-1989
notes 17 deaths [34], 65% of which occurred when the therapeutic dose
was increased. In both reports frequent reasons for death were; the change
to a new batch lot of a non-standardized extract, wrong or inadequate
dosage and insufficient observation time after injection.
Due to the WHO reports the following risk factors must be noticed:
dosage errors;
presence of asthma;
high degree of hypersensitivity;
use of new vials;
injections during exacerbation of symptoms;
use of ß-receptor blockers;
use of ACE-inhibitors.
For hyposensitization emergency equipment must be available and the
methods of its deployment known not only by physicians but also by other
staff members [18].
The risk of side effects can be reduced following certain rules (familiar
to an experienced allergist):
repeated taking of history (symptoms, alcohol, stress, medication
[ß-blocker, ACE-inhibitor], reaction to previous injection);
precise informing of the patient;
optimal compliance of the patient;
use of standardized allergen extracts;
allergen avoidance (most important: pets!) during therapy;
exact procedure (interval, individual dosage, accurate handling
of vials and protocols, strict subcutaneous injection);
observation for at least 30 minutes after injection; in patients
at risk, for longer;
possible antihistamine premedication in risk patients (repeated
anaphylactic rections);
emergency equipment and regular training.
Comments
Before deciding on a hyposensitization therapy several aspects must
be considered:
IgE-related allergic diseases to aeroallergens occur mostly in
young and middle-aged people.
Without hyposensitization rhinoconjunctivitis might evolve into
manifest bronchial asthma.
In perennial allergic diseases allergen avoidance seems crucial.
Insect venom allergies are not restricted to age groups nor to
atopic predisposition. Hyposensitization is potentially lifesaving and
effective in 90% of cases but does not remove the necessity to carry emergency
self-medication.
For hyposensitization the patients must be highly motivated and
cooperative.
Controlled studies showed that specific hyposensitization with standardized
allergens is an effective treatment for IgE mediated allergic diseases.
It is a curative and preventive therapy and helps to economize the consumption
of medicine (Table III).
The disadvantages of hyposensitization include cost, duration and risk
of anaphylactic reactions. Therefore only physicians experienced in allergy
should perform hyposensitization (Table
III).
Specific hyposensitization (also called specific immunotherapy) is
a method of causal treatment of allergic diseases.
Switch from Th 2- into Th 1 reaction pattern in the T cell regulation.
The efficacy of specific hyposensitization has been assessed in controlled
studies.
An allergen extract is obtained by extraction of the active ingredients
of animal or vegetable substances.
All allergen vaccines should be standardized.
Allergen extracts for hyposensitization are either unmodified (aqueous)
or modified chemically, and/or by adsorption to different carriers
(Table II).
Allergoids are chemically modified and have more immunological effects
and less side effects than aqueous, unmodified vaccines.
The vials containing the vaccines have to be labeled with important
patients' data and additional extracts' data, including a designation
of relevant units, shelf-life, therapeutic dosage schedules, and appropriate
methods for storage.
Indications for specific hyposensitization are IgE-mediated allergic
diseases such as allergic rhino-conjunctivitis, allergic asthma and hymenoptera
venom allergy.
Before starting treatment, additional indoor allergens must be reduced
(e.g. removing of pets, eradication of dust mites), otherwise hyposensitization
leads to an allergen overload, which can induce severe allergic reactions.
Patients with atopic eczema should in any case be followed carefully
and treated with low doses.
Hyposensitization therapies with molds and animal hair are the subject
of controversy among allergologists.
The hyposensitization therapy with highly purified insect venoms
is highly effective.
No age limit for hyposensitization with hymenoptera venoms.
Hyposensitization in children follows the same considerations for
diagnosis and treatment.
According to most authors hyposensitization should not be started
in children under the age of 5.
Pregnancy and convulsions are no longer considered to be contraindications.
During hyposensitization atopic symptoms of diseases like rhinitis,
asthma or atopic eczema may be triggered or worsened.
The most dangerous side effect of hyposensitization is systemic anaphylaxis.
For hyposensitization emergency equipment must be available and the
methods of its deployment known not only by physicians but also by other
staff members [18].
The disadvantages of hyposensitization include cost, duration and
risk of anaphylactic reactions. Therefore only physicians experienced
in allergy should perform hyposensitization (Table
III).
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