Page 1272 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1232 Part tEN Prevention and Therapy of Immunological Diseases

control subjects had developed asthma, representing a relative risk intercurrent viral illness, so doses should be delayed if the patient
of 3.8 for untreated subjects compared with the actively treated is unwell or has any signs of active asthma.
group. 22 On a separate note, there is general agreement that SIT should
SIT may also modify the progression of established asthma. not be used in patients with autoimmune disorders or malignant
An early open study using uncharacterized mixed allergen extracts disease. Although there is no hard evidence that SIT is actually
supported this view, with about 70% of treated children losing harmful in these groups, it seems unwise to attempt manipulation
their asthma after 4 years therapy, compared with about 19% of the immune system in such patients, not least because of the
of untreated controls, a result that was sustained up to the age risk that spontaneous and unrelated variations in the autoimmune
of 16 years. The proportion of children whose asthma was severe disorder or cancer may be blamed on SIT. Other medical con-
23
at age 16 years was also much lower in the treated group. In traindications to SIT include significant coexistent cardiac disease,
this period, when clinical trials were conducted differently, well which may be exacerbated by any adverse reactions to SIT. Patients
before the days of ethics committees, Johnstone and Dutton on beta-blockers should also not receive SIT. Although they are
randomized all children attending their clinic between August not at increased risk of adverse reactions, their physiological
1953 and January 1955 to one of four treatments. Neither the response to the cardiovascular component of anaphylaxis will
subjects nor their parents were aware of the treatment being be impaired, and they will not respond to the epinephrine that
given. Compared with those who received placebo or very dilute is used to treat adverse reactions to SIT.
allergens, those treated with the two higher doses of SIT were
much more likely to lose their asthma after 4 years, and among SUBLINGUAL IMMUNOTHERAPY
those whose asthma persisted, the likelihood of having severe
disease was much lower in those who had received active treat- High-dose topical immunotherapy regimes were used in the
ment. Although it would be very difficult to conduct such a first half of the twentieth century but then lost ground to injection
study today, the data are useful in confirming the dose–response immunotherapy in conventional medical practice. Over the past
relationship in SIT and its potential for reducing the duration 20 years, there has been a resurgence of interest in SLIT, which
and severity of asthma. A prospective, nonrandomized, open-label is based on the concept that allergens given via the mucosal
study of SLIT has reported that children with asthma who received surface can induce immunological tolerance, without carrying
SLIT had less asthma compared with those on standard medica- the same risk of systemic reactions that is found with injection
tion after 4–5 years, and this difference persisted for 5 years after SIT. Moreover, SLIT is more appealing to patients, especially to
cessation of treatment. 24 those who cannot easily find time to attend clinic for injection
27
In contrast, there is no current evidence that SIT influences SIT. In animal models, IgE responses to allergens can be reduced
the evolution of established asthma in adults. In part, this reflects or prevented by oral administration of allergen. Most of these
the reluctance of physicians to use SIT to treat patients with models involve feeding in early life to prevent subsequent acquisi-
severe asthma. Studies that have investigated withdrawal of therapy tion of sensitivity, so this is a different scenario from the usual
have reported rapid recurrence of asthma symptoms, although clinical context of treating established allergic disease. The precise
rhinitis symptoms seem to show much more sustained relief mechanisms by which “oral tolerance” is induced remain unclear,
after SIT. 25 but it seems likely that the route of allergen processing and
In summary, there is persuasive evidence that both subcutane- presentation is a critical determinant of the subsequent T-cell
ous and sublingual immunotherapy can modify the course of response (Chapter 6). In mice, locally administered allergen is
allergic disease, by reducing the incidence of new sensitizations, taken up by mucosal DCs and then presented to T cells together
and by preventing or slowing the development of clinical asthma. with IL-12, biasing the response toward a Th1-like profile and
The mechanisms that underlie these observations are not fully away from the pro-IgE Th2 profile. In contrast to the animal
understood. It is likely that a combination of immunological models, the immunological response to SLIT in human studies
and structural alterations is involved. Economic evaluations of has been relatively modest. Some changes have been found in
the benefits of SIT and SLIT need to take on board these preven- skin sensitivity, but most studies have not found any change in
tive effects to arrive at a full cost–benefit analysis. systemic parameters, such as specific IgE, specific IgG, or T-cell
cytokine balance. 28
SAFETY Nevertheless, a body of evidence has accumulated from well-
conducted clinical trials, indicating that SLIT can be effective,
The main factor preventing the wider adoption of SIT is the with up to 30–40% reductions in symptom scores and rescue
29
risk of serious adverse reactions. In general, SIT is quite safe in medication use in seasonal allergic rhinitis. SLIT treatment
patients who do not have asthma, but a significant number of regimes typically involve a rapid buildup phase followed by
deaths have been reported in the United Kingdom and the United treatment about three times per week with rapidly dissolving
States when SIT was used to treat patients whose asthma was tablets containing allergen extracts. Some preparations are sup-
26
unstable. The incidence of systemic reactions in patients receiv- plied in liquid form, with a calibrated dropper. Several large
ing SIT for asthma varies among study series and has been clinical trials of SLIT have shown clinically and statistically
reported to range from 5% to 35%. In contrast, serious systemic significant reductions in symptom and medication scores, sup-
reactions occur after about 1 in 500 injections in patients with porting the conclusions of previous meta-analyses of SLIT, which
rhinitis. Some adverse events are caused by administration of assessed the earlier, less well-designed studies that were individu-
the wrong dose, which underscores the importance of checking ally small and inconclusive. The meta-analysis estimated the
doses carefully before each injection. Others occur during efficacy of SLIT as being about two-thirds of that seen in
changeover from one vial to another. Most allergists, therefore, comparable studies of injection SIT, but the most recent studies
cut back on the dose when changing vials to minimize this risk. have shown levels of efficacy that are equal to the best recent
Systemic reactions are much more likely if the patient has an multicenter trials of injection SIT. However, the efficacy may be