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.