Discussion
The current study is the largest double-blind randomized clinical ILIT
trial to date. Patients with hay fever due to sensitization to both
grass and birch pollen allergens received 5-grass and birch ILIT,
5-grass ILIT (with birch placebo), or birch ILIT (with grass placebo).
The study revealed statistically significant clinical efficacy of ILIT
in all three treatment groups. Participants reported improvements in
RTSS, RQLQ as well as reduced MS in the first pollen season following
ILIT. The effects were sustained throughout the following three
follow-up seasons. We expected that the clinical efficacy of ILIT would
mostly be observed for the targeted allergen, i.e . that patients
receiving birch ILIT would not respond well during the grass pollen
season and vice versa for patients with 5-grass ILIT. Surprisingly,
patients receiving birch ILIT or 5-grass ILIT reported improved clinical
symptoms during pollen seasons for which they had received no treatment.
The clinical data were accompanied and supported by immunological
changes such as an increase in the proportion of Treg cells and birch
allergen included secretion of IL-10 after the treatment, as well as
decreased spontaneous production of the Th2 chemokine CCL17. In
contrast, the increase in the number of Th2 cells and the increased
level of allergen-specific IL-5 production after birch ILIT were
unexpected. As clinical improvement was sustained throughout our study,
we suggest the results are not only due to a placebo effect, although
placebo effects may be very strong in AIT-clinical trials24. The clinical effect did not seem to be mediated by
allergen-specific IgG4, as these antibody levels were not clearly
elevated between pre-ILIT baseline and any of the time points
thereafter. AIT efficacy has, however, often been reported to correlate
with increased IgG4 6. Moreover, in previous grass- or
birch-pollen ILIT studies, only moderate or no changes in IgG4 were
determined 15-19, whereas a significant increase in
allergen-specific IgG4 was determined after ILIT with cat dander
allergen 25. In contrast, the beneficial clinical
responses correlated with an increase in the frequency of Tregs and
increased secretion of IL-10. This potentially inhibitory bystander
effect of Tregs and IL-10 might explain why the improved clinical
outcome was not dependent on the ILIT allergen.
The birch pollen counts in 2014 and 2018 were higher than in 2015, 2016,
and 2017. Fifty-five study subjects received ILIT in 2014 and seventeen
received ILIT in 2015, so differences in pollen count were leveled out.
Patients who received ILIT in 2015 compared well in the following
seasons to patients that received ILIT in 2014. Recall bias is limited
as the patients recorded their RQLQ, RTSS and MS directly after the
birch and grass pollen seasons, which are quite separate in Sweden,
after enrollment, before ILIT and three years after, i.e. four
years in all. Of seventy-two patients receiving ILIT, only two was lost
to follow up after three years.
Most of the AEs were judged as mild or moderate, generally at the
allergen injection site, which is also a normal reaction after SCIT26,27. However, whereas patients receiving ILIT in the
current study reported between none to three AEs, the number of AEs
after SCIT can be up to 40–50. In a large study that analyzed AEs in
1,700 patients who had received SCIT, systemic AEs were reported in
3.3% of the injections 27. Edema and pruritus at the
injection site, flush, urticaria, wheezing, dyspnea, eye pruritus,
headache, and abdominal pain are common (1-10%) or very common
(>10%) with SCIT, whereas oral pruritus, oral edema,
rhinitis, headache, ear pruritus, throat irritation, asthma, abdominal
pain, urticaria, and fatigue are common or very common with SLIT28. ILIT seems to give AEs similar to those with SCIT,
but because ILIT only needs three injections, the AEs can be reduced by
up to 90% compared with SCIT.
One limitation of this study is that it had no true placebo group
because all the participants received ILIT against, at least, one
pollen. This was for ethical reasons as we did not want any patient with
rather severe ARC to be without immunotherapy for four years. The
approach with “active allergen placebo” was suggested in an
ARIA-GA2LEN statement in 2011 29 and
supported by a recent SCIT study where dual-allergic patients were
randomized to receive either grass or birch SCIT. Here, targeted but not
untargeted allergen rhinoconjunctivitis symptoms were reduced in
contrast to our results 30.
AIT renders significant improvements in rhinoconjunctivitis and
conjunctival sensitivity that persist at least seven years after
termination of treatment 7. In addition, AIT can
prevent development of asthma 31,32 and new
sensitizations in mono-sensitized patients 12,33.
After an updosing phase of 7–15 weeks in SCIT, a maintenance phase of
three years with injections every six weeks is typically required to
render long-term tolerance. This long duration is a major problem with
SCIT 7. For SLIT, 55–82% of patients were reported
to abandon the treatment before completing the recommended course of
therapy 34. With only three injections over eight
weeks, ILIT may overcome the disadvantages of long duration of treatment
and poor compliance.
The results of this study add to the hitherto positive studies and
suggest that ILIT is effective and safe as treatment for pollen allergy.
We will follow the patients in this study for symptoms, health-related
quality of life and adverse events in an open study until 2024 (EPN
2017/302-31).
In conclusion, ILIT is an opportunity to make AIT more easily accessible
to patients at a lower cost and less risk. There is a need for further
studies to establish the optimal dose for efficacy and side effects20.