Pros and cons: Should AIT be considered in all patients with allergic
asthma?
Roy Gerth van Wijk1x, Ronald Dahl2
Affiliations:
1 Section of Allergology and Clinical Immunology,
department of Internal Medicine. Erasmus Medical Center, Rotterdam. The
Netherlands.
2Aarhus University, Aarhus, Denmark
xCorresponding author
Roy Gerth van Wijk
Section of Allergology and Clinical Immunology, department of Internal
Medicine. Erasmus Medical Center, Rotterdam. The Netherlands.
Keywords: allergy, asthma, allergen immunotherapy, subcutaneous
immunotherapy, sublingual immunotherapy
Abstract
Allergen immunotherapy (AIT) has gained a permanent place in the
therapeutic arsenal for the patient with allergy. Particularly,
substantial evidence has been established for the efficacy of AIT in
allergic rhinitis. A hallmark of AIT is it disease modifying effect
resulting in persistent benefit after the treatment has been terminated.
Both the subcutaneous and sublingual mode of administration appear to be
safe. It is, however, a matter of debate whether AIT can be implemented
for patients with asthma. EAACI and GINA guidelines recommend sublingual
AIT in house dust mite driven asthma. The question however remains
whether the different available forms of AIT should be used for allergic
asthma in general.
PRO (707 words)
Asthma is a heterogeneous disorder, with many pathophysiological
mechanisms underlying the typical clinical presentation. The term
“asthma” could be considered as an umbrella diagnosis. Several
components are involved in the asthma disease process and “one size”
does not fit to all individuals. Each patient should be evaluated for
the clinically relevant factors involved, including atopic
sensitisation. Provided the diagnosis of asthma is correct, and the
specific allergy is present, and a therapeutic extract containing the
relevant allergen components is used, then AIT may result in clinical
improvement of asthma. The role of AIT in asthma has been addressed in a
recent European Academy of Allergy and Clinical Immunology (EAACI)
guideline(1) and systematic review(2).
Two important outcomes of AIT were mentioned in the position paper
endorsed by The World Health Organization, namely the ability to induce
tolerance toward the allergen in question and to change the natural
history of the allergic disease(3). Both subcutaneous immunotherapy
(SCIT) and sublingual immunotherapy (SLIT) show efficacy and reduce
symptom scores and medication use. In addition, SCIT and SLIT improve
quality of life, and induce sustained clinical effect after three or
more years of treatment. A disease modifying effect is seen based on
changes in specific immunologic markers(4).
The persistence of clinical effect also following treatment end is
remarkable and not seen for other asthma treatments. The tolerance
induced seems to be based on a modification of the immunological
processes leading to clinical asthma. This involves a change in T cell
response from an allergic type Th2 dominance to a Th1 dominance. This is
reflected by the cytokines produced after allergen contact. Also, an
induction of specific regulatory T cells has been documented. Recently,
the role of immunosuppressive regulatory B cells and IL-10 producing
innate lymphoid cells (ILCs) in AIT has been documented (5).
The increase in our understanding of the mechanisms behind AIT (figure
1) paves the way for innovation and further improvement of AIT.
Although there are safety concerns about SCIT, the European Survey on
Adverse Systemic Reactions in Allergen Immunotherapy (EASSI) evaluated
both SCIT and SLIT, in a total of 4316 patients. Hundred and nine
systemic reactions were reported, 97 of them (89%) concerning SCIT, the
most frequent being urticaria, rhinitis, dyspnoea, and cough. Adrenaline
was administered in 17 systemic reactions; however, only 65% of such
reactions were classified as anaphylaxis(6). To minimize the risks of
systemic reactions, physicians should be experienced and well trained.
The recent EAACI guideline about HDM driven asthma recommends AIT as an
add‐on to regular asthma therapy for adults with controlled or partially
controlled allergic asthma. HDM SCIT is recommended for adults and
children, and SLIT drops are recommended for children. Moreover, the
Global strategy for asthma (GINA) management and prevention 2021 (8),
states that adding SLIT should be considered for adult patients with
allergic rhinitis and sensitized to house dust mite with persisting
asthma symptoms despite low-medium dose ICS-containing therapy, provided
FEV1 is > 70% predicted.
In clinical trials SLIT for house dust mite allergy was found to reduce
moderate/severe exacerbations, improve asthma symptoms and improve
quality of life. The treatment also significantly reduced the need for
inhaled corticosteroid. This may be related to a concomitant improved
lung function, a reduction of the response to allergen provocation(9)
and a decrease of eosinophilic bronchial inflammation.
In conclusion (figure 1), properly diagnosed and well-selected patients
with allergic asthma may benefit from AIT, provided that patients are
treated with well characterized and standardized extracts containing the
relevant allergens. AIT is the only treatment that may have a long term
immune modulating effect in asthma. In clinical terms, this could be
seen by a persistence of clinical improvement several years after
termination of AIT. The choice for a specific AIT product should always
be based on the availability of high quality efficacy and safety data.
PRO
- AIT with HDM tablets reduces the risks of exacerbations,
- AIT with HDM tablets reduces the amount of ICS needed for asthma
control,
- AIT is the only disease modifying treatment resulting in a persistent
reduction of symptoms,
- AIT is a safe treatment with few severe side effects in SCIT and
transient mild side effects in SLIT,
- The increasing understanding of the immunological mechanisms behind
AIT paves the way for innovative and improved AIT.
CON (669 words)
In 110 years allergen immunotherapy has evolved as one of the
therapeutic pillars for allergic patients with rhinoconjunctivitis. The
question has to be addressed whether this is also true for the treatment
of allergic asthma. The EAACI guideline for house dust mite-induced
(HDM) asthma recommends SCIT for adults and children(1). However, using
the GRADE approach the authors consider the evidence of low quality. A
significant heterogeneity of HDM SCIT studies was observed. Moreover,
due to lack of evidence no recommendation could be provided for the use
of HDM SCIT to decrease exacerbations, improve asthma control and lung
function, or to decrease nonspecific airway hyperresponsiveness. SLIT
drops were only recommended for children, but again based on studies
with low-quality evidence (1). At present, SLIT drops are not on the
market in Europe and the US. Based on a large RCT from Virchow, HDM
sublingual tablets are recommended for adults to prevent asthma
exacerbations(7). This RCT can be considered as a landmark study. There
are, however, no data yet supporting efficacy of HDM tablets in
children. SLIT tablets for children are under investigation.
The recent EAACI systematic review focusing on different allergens
demonstrated efficacy of AIT in general with reductions in short-term
symptom and medication scores, whereas a subgroup-analysis confirmed a
beneficial efficacy for SCIT but questionable effects for SLIT(2). It
was however, stated that these findings needed to be interpreted with
caution as the majority of trials are of high or uncertain risk of bias.
The questionable effect for SLIT confirms an earlier Cochrane study
which was hampered by lack of data for important outcomes such as
exacerbations and quality of life and by use of different non-validated
symptom and medication scores(10)
In this review, few studies were focused on studies were focused on
asthma caused by pet and fungal allergy. Efficacy for cat and dog
allergy was demonstrated, while efficacy for fungal asthma was suggested
but not confirmed(2). Moreover, the animal allergy subgroup analysis was
mainly based on older small SCIT studies conducted several decades ago.
AIT aims to change the natural course of the disease. Despite
observational studies suggesting long-term efficacy, randomised
long-term studies have not yet been conducted in asthmatics, neither
with SCIT nor with SLIT(1).
Cost-effectiveness was also addressed in the EAACI guidelines(11).
Although cost-effectiveness over standard treatment was suggested, all
studies were of low methodological quality. One SCIT and two SLIT
studies only satisfied the eligibility criteria. One study only focused
on asthma without rhinitis. Cost-effectiveness could not be calculated
as no attempt was made to convert outcome measures in a general quality
of life measure such as quality of life adjusted life years (QALYS). The
second study calculated QALYS but did not characterise the uncertainty
of the estimate. In addition, the third study did not measure QALYS(11).
Finally, some other caveats. Clinicians should be aware that
sensitization to an allergen by itself does not justify AIT. The
allergen should be considered clinically as a major trigger. Moreover,
AIT is demanding much from both patients and health care providers. The
long duration of treatment and the slow onset of treatment effects may
compromise adherence to treatment.
In conclusion (figure 1) , although good results have been obtained with
HDM sublingual tablets in adult asthmatic patients, the evidence for AIT
in asthmatic children is weak. Moreover, more studies are needed to
assess long-term efficacy, to evaluate AIT with other allergens,
particularly animal allergens and fungi. High-quality cost-effectiveness
studies are needed to meet the requirements of national health care
systems.
CON
- Robust effects have been demonstrated with HDM tablets in adults only,
but evidence for other routes (SCIT) and methods (SLIT drops) of
administration is weak,
- Evidence for the efficacy of AIT with other allergens, such as animal
allergens and fungi is limited, There is an urgent need to establish
solid evidence for AIT in asthmatic children,
- Good data on sustained or long-term efficacy for AIT in asthma are not
available yet,
- The number of cost-effectiveness studies is low. The methodological
quality of available studies is limited.
CONFLICT OF INTEREST
Both authors declare no conflict of interest.