Subcutaneous Immunotherapy: clinical aspects
Anthony J Frew MD FRCP
Professor of Allergy & Respiratory Medicine, Royal Sussex County Hospital,
Brighton BN2 5BE UK
Introduction
Specific allergen immunotherapy (SIT) involves administration of allergen extracts to
patients with allergic conditions in order to modify or abolish their symptoms. SIT is
specific, in that it targets those allergens identified by the patient and physician as
responsible for symptoms, but does not affect sensitivity to unrelated allergens. While
the precise mechanisms involved remain uncertain, there is a substantial body of
clinical evidence and practice to support the use of SIT. Before deciding to use SIT,
the patient’s condition needs to be carefully assessed, with particular regard to allergic
triggers. In addition, since the course of treatment is lengthy and relatively expensive,
there must also be an assessment of the risks and costs as compared to symptomatic
treatment with antihistamines and topical corticosteroids.
Immunotherapy was first developed at St Mary's Hospital London 100 years ago [1]
and many of the basic principles described by Noon and Freeman remain valid today.
In standard subcutaneous immunotherapy (SCIT), patients receive a course of
injections, starting with a very low dose of allergen, and building up gradually until a
plateau or maintenance dose is achieved. Maintenance injections are then given at 46 weekly intervals, usually for 3 years. The updosing phase is usually given as a series
of weekly injections, but several alternative induction regimes have been tried, some
giving several doses on each day then waiting a week before giving a further series of
injections (cluster protocol), while others give the whole series of incremental injections
in a single day (rush protocol).
Mechanisms of immunotherapy
Several mechanisms have been proposed to explain the beneficial effects of
immunotherapy. Whether given by injection or sublingually, SIT induces changes in Tcell and antibody responses. The challenge for clinical scientists has been to work out
which of the observed changes drive the clinical benefit, and which are just
epiphenomena. Allergen-specific IgE levels rise temporarily during the initial phase of
SIT, but fall back to pre-treatment levels during maintenance therapy [2]. The
immediate weal and flare response to skin testing usually reduces during the initial
phases of SIT but this effect is relatively small compared to the degree of clinical
benefit. In contrast, the late-phase response to skin testing is virtually abolished after
successful SIT. Similar patterns are observed for late-phase responses in the nose
and airways [3]. SIT also induces allergen-specific IgG antibodies, particularly
antibodies of the IgG4 subclass. In most studies IgG correlates better with the dose of
allergen that has been given, rather than with the degree of protection achieved. There
has been a recent resurgence of interest in a possible inhibitory role of specific IgG
antibodies in grass pollen immunotherapy [4], in particular, the timecourse of this
effect raises the possibility of sIgG antibodies interfering with IgE-dependent cytokine
secretion from mast cells or facilitated antigen presentation to T cells.
1
In nasal and skin allergen challenge models, successful SIT is accompanied by a
reduction in T-cell and eosinophil recruitment in response to allergen. In parallel,
there is a shift in the balance of Th1 and Th2 cytokine expression in the allergenchallenged site. Th2 cytokine expression is not affected but there is an increased
proportion of T-cells expressing the Th1 cytokines IL-2, IFN- and IL-12 [5-7]. After
venom SIT, there is induction of allergen-specific CD4+ T-regulatory cells which
express CD25, Fox p3 and IL-10, as well as a shift in Th1:Th2 balance [8,9]. Similar
findings have also been reported following SIT with inhalant allergens [10]. IL-10 has
several relevant actions, including downregulation of T-cells and induction of
allergen-specific IgG4 antibodies, which may explain the IgG4 response to SIT. The
IgG4 response should probably be viewed as a surrogate marker of IL-10 induction,
rather than the beneficial mechanism of SIT [11]. Overall, it is clear that SIT has a
modulatory effect on allergen-specific T-cells, and this is probably why clinical and
late-phase responses are attenuated without suppressing allergen-specific antibody
levels or immediate allergic responses.
CLINICAL INDICATIONS
SIT for venom hypersensitivity
Anaphylaxis to hymenoptera venom is relatively rare, but can be fatal. Precise
figures are hard to come by, but a figure of at least 40 deaths per year in the USA
has been cited. Venom immunotherapy can reduce the risk of fatality and improve
the patient’s quality of life by allowing them to go out and work or play without
worrying about the possibility of a serious allergic reaction. Given the relatively small
number of fatalities, the main impact of VIT is on people’s quality of life. After
completing VIT, there is a residual risk of systemic reactions of approximately 10%,
but when reactions do occur to stings after VIT, they are typically mild. Patients who
receive VIT should be supplied with anti-allergic medication for use in the event of a
sting during or after therapy. Some allergists recommend providing injectable
epinephrine during therapy, but this is not necessary once the patient has reached
the maintenance dose of SIT.
SIT for allergic rhinitis
SIT is a useful treatment for allergic rhinitis, especially when the range of allergens
responsible is narrow. The allergic basis of the rhinitis should be carefully assessed
both on history and on skin tests or blood tests, and other causes of nasal symptoms
should be excluded. In patients with persistent non-seasonal rhinitis, it can be
extremely difficult to determine whether the patient’s symptoms are truly due to allergy,
or whether they have non-allergic rhinitis, and just happen to be sensitised to an
allergen that is not clinically relevant. This difficulty in determining clinical relevance
contributes to the reported lower degree of efficacy in SIT trials with perennial
allergens, as compared to SIT for seasonal allergies.
The effectiveness of SIT in intermittent (seasonal) allergic rhinitis has been confirmed
in many trials, using grass, ragweed and birch pollen extracts [12]. Importantly, SIT is
effective even in patients whose severe seasonal rhinitis is resistant to conventional
drug therapy [13]. Importantly, patients with multiple allergic sensitisation respond at
least as well as those who were monosensitised to grass pollen.
2
The benefits of one year’s treatment wear off quickly [14], but three years therapy
gives lasting benefit [15]. Less well controlled data show that the effects of SIT can
persist for many years after discontinuing therapy [16]. This contrasts with
conventional drugs, whose effects wear off very soon after discontinuing therapy. The
benefits of SIT for perennial rhinitis are less than for seasonal rhinitis, but clinical trials
have shown a definite benefit in appropriately selected subjects.
SIT for asthma
Immunotherapy has been widely used to treat allergic asthma, although the
introduction of effective inhaled therapies has changed the general pattern of asthma
care. Concern over adverse reactions, including a small number of fatalities, has led
some countries (e.g. UK) to restrict the use of SIT for asthma treatment, although
asthma remains a common indication for SIT in many parts of North America and
continental Europe [17,18].
Current drug therapies for asthma aim to suppress airways inflammation and relieve
bronchospasm. None of these treatments are curative and asthma recurs rapidly on
ceasing treatment. However, SIT remains controversial as a treatment for asthma
because of its potential for adverse effects. The efficacy of SIT in adult asthma has
been assessed in many trials over the last 65 years. The results of these studies have
often been difficult to interpret, either because poor quality allergen extracts were used
or because of poor study design.
The main drawback in using SIT to treat asthma is the risk of serious adverse
reactions. The vast majority of fatal reactions to SIT have occurred in patients with
asthma, and while asthma is not an absolute contraindication, it is clear that patients
with unstable asthma should not be offered SIT, and caution should be exercised in
anyone with an increased level of asthma symptoms or transiently reduced peak flow
rates.
Effects on natural history of allergic disease
Children often start with a limited range of allergic sensitivities and progress over time
to develop IgE against a wider range of inhaled allergens. Treatment with SIT may
limit this tendency to acquire new sensitisations [19] although the clinical benefit of this
preventive effect is not clear. A proportion of patients with allergic rhinitis develop
asthma each year. This annual rate of progression has been estimated at 5% in
college students [20] but this is perhaps surprisingly an area of considerable
ignorance. SIT may modify the natural history of asthma in children who are known to
be atopic but have not yet developed asthma. Only limited data is available to support
this proposition. In the key study, a group of 205 children aged 6-14, without previously
diagnosed asthma, were treated with SIT for birch or grass pollen allergy in an open
randomised design. Three years after completing treatment 45% of the untreated
group had developed asthma while only 26% of the treated group had asthma. These
results have been sustained out to seven years after completing therapy [21]. SIT may
also modify the progression of established asthma. An early open study using
uncharacterised mixed allergen extracts supported this view, with about 70% of
treated children losing their asthma after four years therapy, compared to about 19%
of untreated controls, a result which was sustained up to the age of 16 years [22]. In
contrast, there is no current evidence that SIT influences the evolution of established
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asthma in adults.
Safety of SIT
The most obvious risk of SIT is provocation of systemic allergic reactions. In the UK
twenty-six fatal reactions due to SIT were reported between 1957 and 1986 [23]. In
almost all cases these patients were receiving SIT to treat their asthma. Similarly, in
the AAAAI inquiry into SIT-associated deaths, asthma appeared to be the cause of
death in most of the fatal cases [24,25]. The incidence of systemic reactions in
patients receiving SIT for asthma has been reported to range from 5% to 35%.
Separately, there is some concern about the use of immunomodulatory treatments in
patients with autoimmune disorders, immunodeficiency syndromes or malignant
disease. While there is no hard evidence that SIT is actually harmful to these patients,
some clinicians feel uncomfortable about manipulating the immune system in such
patients, not least because of the risk that spontaneous and unrelated variations in the
autoimmune disorder or cancer may be blamed on SIT.
Future directions
There is scope to improve conventional SIT. Possible avenues include the use of
recombinant allergens, various forms of allergenic molecules folding variants and
other modifications of the physical structure which may also improve the safety of
SIT [26]. Since the epitopes recognised by IgE molecules are usually threedimensional whereas T-cell epitopes are short linear peptide fragments of the
antigen, it should be possible to use peptide fragments of allergens to modulate T
cells without risking anaphylaxis. Alternatively, DNA vaccines may be used, either by
a general approach, using CpG oligodeoxynucleotides which mimic bacterial DNA,
and stimulate Th1-type cytokine responses, or a more specific approach using
allergen-specific naked DNA sequences as vaccines.
Conclusions
SCIT has been used for over a century, and is clinically effective in patients with
rhinitis or asthma whose symptoms are clearly driven by allergic triggers. Although we
are still unsure exactly how SIT works, it induces regulatory T cells that damp the
response to allergen exposure in sensitised subjects. When used in appropriately
selected patients, SCIT is effective and safe, but care is needed to recognise and treat
adverse reactions. Future directions in SIT will include the development of better
standardised vaccines, and the use of recombinant allergens, both of which should
improve the safety profile of SIT.
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