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MJA 1997; 167: 540-544
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Introduction - Atopy, allergens and asthma - Rationale for using immunotherapy for asthma - Clinical trials - Allergen extracts and route of administration - Adverse effects - Practical aspects of administering immunotherapy - References - Authors' details
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Introduction |
Specific allergen immunotherapy (desensitisation,
hyposensitisation) is the technique of treating IgE-mediated
disease with increasing doses of an allergen in order to decrease
sensitivity to that allergen. First used early this century, 60
million patients annually are now treated with immunotherapy
throughout the world.
The only absolute indication for immunotherapy is a life-threatening reaction after a Hymenoptera (bee or wasp) sting; all other indications are relative (see indications and contraindications for immunotherapy). Many randomised controlled trials have shown that hayfever caused by airborne pollens and house dust mite responds to this therapy.1 The use of specific allergen immunotherapy in asthma remains controversial. Despite this, the Thoracic Society of Australia and New Zealand and the Australasian Society of Clinical Immunology and Allergy believe that all strategies which may impact on the morbidity and mortality of asthma should be assessed. The cost-effectiveness of this therapy also needs to be addressed in the context of the total cost of asthma in Australia, the mid-estimate of which in 1991 was $652 million (National Asthma Campaign, 1992). We present an overview and do not cover all aspects of this subject. Interested readers are referred to recent reviews.1-9 |
Atopy, allergens and asthma |
Allergy is best defined as an exaggerated response on exposure to an
allergen following prior exposure, and mediated by an immune
reaction involving IgE. The same clinical picture may result from
non-immune mechanisms.
Atopy is an increased tendency to IgE-based sensitivity resulting in production of specific IgE antibody to common environmental allergens, such as house dust mite, pollens, moulds or animal danders. This sensitisation occurs in genetically predisposed people after exposure to low concentrations of allergen; cigarette smoke and viral infections may assist in the sensitisation process. About 40% of the population is atopic, and about half of this group develop clinical disease ranging from trivial rhinitis to life-threatening asthma. After sensitisation, continuing exposure to allergens leads to a significant increase in the prevalence of asthma.10 Ninety per cent of children and 80% of adults with asthma are atopic.10 Once sensitisation has occurred, re-exposure to allergen is a risk factor for exacerbations of asthma.11 Effective management of allergic asthma includes pharmacological therapy and allergen avoidance. For example, avoiding dust mite allergen can reduce symptoms and the need for medication. |
Rationale for using immunotherapy for asthma |
Asthma is an inflammatory disease characterised by the presence of
cells such as eosinophils, mast cells, basophils, and CD25+ T
lymphocytes in the airway walls. There is close interaction between
these cells, because of the activity of cytokines which have a variety
of communication and biological effector properties. Chemokines
attract cells to the site of inflammation and cytokines activate
them, resulting in inflammation and damage to the mucosa.12 With chronicity of the process,
secondary changes occur, such as thickening of basement membrane and
fibrosis.13
An immunological reaction to allergen is the initiating event of airway inflammation in many cases of asthma.14 Continued exposure to allergen results in chronic inflammation. Current therapy aims to suppress this inflammation with inhaled corticosteroids, sodium cromoglycate, or nedocromil sodium, all of which interfere with the cellular and cytokine interactions by diverse mechanisms, but do not address the initiating event in allergic asthma. By withdrawing the allergen or altering the immune response to allergen, it is theoretically possible to control the allergic trigger of asthma. Immunological changes have been described after immunotherapy. These include an initial rise in specific serum IgE, followed by a fall, and a rise in specific IgG ("blocking antibody"). Specific IgG titres correlate poorly with the degree of protection. Immunotherapy leads to a reduction in mediator release from mast cells in vitro, alterations in lymphocyte subsets, and a downregulation of IL-4 production from T cells.15 Several studies have shown a reduction in inflammation and a decrease in bronchial hyperresponsiveness after immunotherapy.1,16,17 There are strong theoretical arguments why immunotherapy should be used early in the course of the disease, before irreversible secondary changes such as fibrosis have occurred. Further, data are emerging to suggest that immunotherapy may also influence the progression of clinical disease.3,7 Immunotherapy should not be regarded as an alternative to established forms of preventive therapy, as recommended by the National Asthma Campaign.18 A systematic cost-benefit analysis of immunotherapy has not yet been undertaken. |
Clinical trials |
There have been numerous randomised placebo- controlled
double-blind trials of immunotherapy for asthma. Comparison of
these trials is difficult, not only because of the inherent problems
of trials involving asthma (such as standardisation of inclusion and
outcome criteria), but also because of differences in allergen
extracts and dosage regimens. A meta-analysis can address some of
these difficulties, and has recently been applied to 20 randomised
controlled trials of immunotherapy for asthma in both adults and
children.19 This
meta-analysis found a clinically useful improvement from
immunotherapy with house dust mite and with other allergens (see
Box below). It concluded that immunotherapy is a treatment option in highly
selected patients (discussed more fully below) with allergic
asthma.
The reviews cited in this position paper,1-9 the meta-analysis19 and further controlled studies published in the last five years20-24 provide references to the most important trials of immunotherapy. |
Allergen extracts and route of administration |
Although several routes of allergen delivery have been used in
immunotherapy, only subcutaneous injection has been studied in
detail and shown to be effective. Giving allergen extract
sublingually is not recommended as studies have failed to show
long-term efficacy.25
Trials with giving birch pollen orally appeared promising, but large
doses were required and there was a high incidence of side effects.
Further studies of oral immunotherapy using modified preparations
are under way. Intranasal administration of pollen extracts
resulted in an unacceptable level of side effects. Local bronchial
immunotherapy with mite extract in patients with asthma has been
studied in a controlled trial but failed to produce significant
clinical improvement.26
Most allergen extracts used in Australia for immuno therapy of inhalant allergy are alum-precipitated. Such preparation slows the absorption of allergen, reducing the risk of serious anaphylaxis and providing sustained immune stimulation. There is no reliable standardisation of biological activity for many allergen extracts used in Australia. Mass and concentration of active material are not useful guides to biological activity. The concentrations of the slow-release (alum-precipitated) preparations are expressed in "protein nitrogen units" and not biological activity. Aqueous preparations of some allergens, including Dermatophagoides pteronyssinus, are standardised against a WHO standard and are extremely potent. Their use in asthma should be restricted to specialist centres. |
Adverse effects | |
Local reactions | Mild swelling and erythema at the site of the injection is to be expected. It may persist for 24 hours or more and is not a cause for concern. A more severe reaction over 50 mm in diameter is an indication for reduction in the subsequent dose. |
Systemic reactions |
These include sneezing, bronchospasm, urticaria and, in more severe
cases, anaphylaxis with hypotension and collapse. They must always
be regarded seriously. Although they usually occur within 30 minutes
of the injection, they may be delayed for several hours with the use of
alum-precipitated preparations. Recent data from the UK estimate
that the incidence of severe systemic reactions was 1 in 500
injections,1 but most
occurred with aqueous extracts, and alum-precipitated extracts
appeared to be much safer. The incidence of anaphylaxis with Allpyral
(Bayer, Pymble, NSW), the alum-precipitated material available in
Australia, was reported to be 1 in 27 854 courses of treatment, and of
anaphylaxis and/or bronchospasm, 1 in 14 998 courses of treatment.27
The Committee on the Safety of Medicines, in the United Kingdom, reported in 1986 that in the 29 years from 1957 to 1986 during which 1 459 273 courses of treatment were given, there were 29 deaths from immunotherapy -- 16 in patients where the indication for therapy was asthma.27 Highly purified and potent aqueous extracts were involved in most of these deaths, and no deaths were reported with the Allpyral extract. Subsequent reports indicated a much lower incidence of anaphylaxis and deaths in France and the US,28,29 where one major difference in practice is that treatment is administered by specialists with expertise in the area. In Australia, five deaths from immunotherapy were reported to the Adverse Drug Reactions Advisory Committee in the 21 years from 1972 to 1993. Four were in patients with asthma, and in each case there was a divergence from recommended procedure. |
Long term adverse effects | There is no increase in the prevalence of vasculitis, autoimmune disease or monoclonal gammopathies during or after immunotherapy.30 Further, there is no evidence that long term worsening of asthma occurs with immunotherapy. |
Practical aspects of administering immunotherapy |
These guidelines relate to specific allergen immunotherapy for the
treatment of asthma in patients with clinical manifestations and/or
need for treatment of ongoing bronchial hyperreactivity.
The decision to prescribe immunotherapy is based on appropriate patient selection, appropriate antigen selection, and whether potential benefits outweigh associated risks. Only a practitioner or team with training and experience in the management of both asthma and immunotherapy should make the decision. Suitably qualified practitioners include thoracic physicians with training and expertise in allergy, or clinical immunologist/allergists with training and expertise in asthma. It is the responsibility of the supervising consultant to (a) decide whether a patient needs to be treated in a hospital, and (b) ensure that the medical practitioner giving immunotherapy receives written instructions on patient assessment and immunotherapy protocol. Informed consent according to currently accepted guidelines must be obtained from patients before starting immunotherapy. Immunotherapy should be given only by a medical practitioner familiar with immunotherapy, conversant with resuscitative procedures, and in a setting where the following resuscitation equipment is immediately available: adrenaline 1:1000 for intramuscular use (adrenaline is the drug of choice for the immediate management of systemic reactions to immunotherapy), oxygen, an inflatable bag and mask ventilator, a nebuliser and bronchodilator nebuliser solution, needles and tubing for intravenous access, intravenous fluids suitable for volume replacement, parenteral antihistamine, and parenteral corticosteroid. The practitioner and a second appropriately trained health care professional should be present during immunotherapy to assist if resuscitation is required. Each patient requires an individual dosage schedule according to the degree of sensitivity and clinical reaction to the injections. The principle of therapy is to start with a small dose and gradually increase it as tolerated. Supervising consultants will have the training and experience necessary to determine the starting dose and appropriate schedule. Flexibility in dosage is essential and rigid adherence to predetermined dosage schedules is inappropriate.
Extracts should be stored in a refrigerator at 4 Every patient should be assessed clinically on each occasion before an injection is given , with particular attention to stability of asthma as indicated by peak flow charts, intercurrent illness, reaction to the last injection and any change in medication. Spirometry or peak flow meter readings must be taken before injection and, if more than 20% below the best recent recorded reading for that patient, the injection should not be given. The readings should be repeated 30 minutes after the injection and immediately any lower respiratory symptoms arise during the period of observation -- a fall of 10% or more is an indication for reducing the dose of the next injection. The medical practitioner must be responsible for selecting the dose and having it checked by a second health professional. Injections are given subcutaneously, a suitable site being the tissue overlying the triceps muscle group. After introducing the needle, and before starting the injection, the plunger should be withdrawn gently to ensure that the needle is not placed intravenously. There is no consensus about the optimal time that a patient must remain under observation . However, we recommend 45 minutes, as serious reactions after that time are rare. Reactions may be delayed with alum-precipitated preparations but they are usually minor. Before discharge patients should be examined to record the size of the local reaction, ensure that there are no signs of a systemic reaction, and to repeat spirometry or peak flow readings. Patients must not engage in strenuous physical exercise or take hot baths or saunas for six hours after the injection. Patients should monitor their peak flow at home ; excessive variability would indicate a need for re-evaluation of asthma and immunotherapy. A local swelling larger than 50 mm requires a reduction in dosage. Patients should be instructed to measure the diameter of any local reaction should it increase in size after leaving medical supervision, and report this before the next injection. Some practitioners "cover" therapy by giving prophylactic antihistamines to reduce the local reactions. This practice may make it difficult to judge the effects of therapy, both locally and systemically, and to modify dosage accordingly. It may also block the initial manifestations of an anaphylactic reaction. Use of this practice is a matter of judgement, but if prophylactic drugs are used use must be consistent. Injection schedules vary with individual patients, but the Allpyral preparations are administered every 1-2 weeks until a maintenance dose is reached. Maintenance injections are administered every 2-4 weeks. It should be re-emphasised that immunotherapy schedules are individualised and fixed schedules are not recommended, particularly when aqueous extracts, which are becoming more readily available in Australia, are used. The duration of therapy for optimal management is unknown at present. With bee and wasp venom immunotherapy, there is evidence that five years of maintenance injections will provide long term protection in almost all patients. There is no corresponding evidence in inhalant allergy and practice varies. Dust mite injections are often continued for 2-3 years if there is a response, and preseasonal immunotherapy with grass pollen is repeated for 2-3 years. |
References |
|
Australasian Society of Clinical Immunology and Allergy,
Melbourne, VIC.
No reprints will be available. Correspondence: Dr D Gillis, Honorary
Secretary, PO Box 204, Mt Albert, VIC 3127.
Ronald S Walls, Robert J Heddle, Mimi L K Tang, Ben J Basger, Graham O Solley and Guan T Yeo. Optimising the management of allergic rhinitis:
an Australian perspective Med J Aust 2005; 182 (1): 28-33. [Clinical Update] <http://www.mja.com.au/public/issues/182_01_030105/wal10248_fm.html>
Michael S Gold and Andrew S Kemp. 6. Atopic disease in childhood Med J Aust 2005; 182 (6): 298-304. [MJA Practice Essentials – Paediatr] <http://www.mja.com.au/public/issues/182_06_210305/gol10313_fm.html>
John M Weiner. Allergen injection immunotherapy Med J Aust 2006; 185 (4): 234. [MJA Practice Essentials — Allergy] <http://www.mja.com.au/public/issues/185_04_210806/wei10219_fm.html>
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C , clearly marked
with the patient's identifier(s) and replaced in the refrigerator
immediately after use. Before injection, the extract should be
examined visually and discarded if its appearance has changed. The
contents of the bottle should be mixed well to avoid variation in
dosage. When changing to a new batch of unstandardised extract (such
as Allpyral), the first dose should be reduced by 25% to take account of
possible variation in biological activity of the preparations. Each
patient should have his or her own individual vial of extract -- laws in
some States forbid multiple use of vials for different patients.