A Silver (Birch) Bullet for Children With Tree Pollen Allergy: Single Allergen Immunotherapy With Birch Extract Protects Across the Birch Homologous Group Pollen Season

Abstract

Allergic rhino-conjunctivitis (ARC) is common in children and markedly impairs quality of life. Children with ARC not only suffer significant morbidity but also face a threefold higher risk of developing asthma [1]. Tree pollens are a major cause of seasonal ARC in Europe and parts of North America. Significant among these is birch pollen, with sensitisation rates in 14 European countries estimated generally at 24%, but as high as 54% in selected parts of Northern Europe [2, 3]. In these regions, the birch homologous group (incorporating birch, hazel, alder, hornbeam, and oak) is characterised by Bet v 1-homologous allergens that lead to a high degree of IgE cross-reactivity of the immune response to other tree pollens within the group. This cross-reactivity confers a longer overall pollen season and extends the geographical region triggering symptoms [4].

Due to treatment burden, cost, and potential systemic reactions, allergen immunotherapy (AIT) is generally reserved for non-response to allergen avoidance combined with medical therapy. While symptoms of ARC can be ameliorated with medical therapies, only AIT can modify its natural history. There is also evidence to suggest AIT for ARC can prevent the ‘atopic march’ toward the development of new allergic sensitisations and incident asthma [5]. Given these considerations, it could be argued that greater consideration should be given to the use of AIT in ARC, particularly in children. However, regarding tree pollen immunotherapy, there is currently a lack of consensus regarding monotherapy with birch pollen extract versus multiple pollen extracts, and consequent regional variation in practice [6].

Investigations of sublingual immunotherapy (SLIT) birch pollen tablet (SQ-tree SLIT tablet) have previously culminated in a Phase III Randomised Controlled Trial RCT in 634 allergic individuals, aged 12 and above, which demonstrated efficacy over placebo with the use of 6–9 months of pre- and co-seasonal treatment [7]. In that study, both adolescents (12–17 years) and adults experienced substantial reductions in symptoms and medication use during birch and tree pollen seasons.

In this issue of Allergy, Gappa et al. [8] report their results from a paediatric Phase III RCT of pre- and co-seasonal birch pollen SLIT versus placebo in 952 children and adolescents (5–17 years) in Europe and North America with moderate to severe seasonal AR due to birch pollen allergy. This is the first large, double-blind Phase III RCT in a paediatric population with tree pollen SLIT (Table 1 provides a comparison of this trial to previous randomised studies). The primary outcome was positive, with the trial finding a significantly greater improvement in combined symptom and medication-use scores with AIT compared to placebo during the birch pollen season. Although primarily focused on clinical outcomes, there were also noteworthy sequential increases in birch-specific IgE, IgG4, and IgE-BF among participants receiving active treatment, consistent with identified biomarkers of immunological efficacy, and affirming clinical efficacy rather than placebo effect [9].

Additional analyses yielded valuable insights. First, similar benefits during birch pollen season were seen in both participants who were mono-sensitised to birch pollen alone as well as participants who were also poly-sensitised to other related tree pollens, thus broadening the applicability of the trial results. Second, birch pollen AIT also attenuated AR symptoms during oak pollen season—complementing findings from other studies that indicate therapeutic cross-reactivity across the birch homologous group to alder and hazel seasons [7, 10, 11]. Thirdly, birch pollen AIT reduced symptoms across the entire tree pollen season, consistent with results from the previous adult and adolescent study [7]. The clinical relevance of this important finding lies in the substantially longer duration of the tree pollen season (76–77 days) when compared to the birch pollen season (23–28 days) observed during the two recruitment periods (Figure 1). The results therefore provide strong support for the immunotherapy strategy of employing birch pollen extract as a representative allergen for pollen from across the birch homologous group.

The safety of the birch extract was generally excellent, apart from one episode of anaphylaxis following first dose administration which necessitated adrenaline use and discontinuation of treatment. To our knowledge, only two severe systemic reactions have been reported in all the studies of SLIT for children, both occurring with the first dose, highlighting the importance of initial dosing under medical supervision.

In summary, this is the largest birch pollen immunotherapy trial to date, with robust positive results extending efficacy and safety data in children, down to the age of five. It adds further to data that single extract birch pollen immunotherapy confers protection across multiple birch homologous group tree pollens, amplifying the temporal benefit and extending geographical coverage. This approach provides an elegant and efficient targeted therapy for tree pollen allergy.

ED declares speaker fees from GSK, Boehringer Ingelheim, Sanofi; unrestricted research funding from AstraZeneca in conjunction with Optimum Patient Care Global Ltd, and travel grants from Novartis, Menerini. MH has received unrestricted grants, speaker and consultancy fees from Glaxo Smith Kline, Astra Zeneca, Novartis, Teva, Sanofi, Chiesi and Stallergenes, unrelated to the current work, and paid to his employer Alfred Health. ROH declares no relevant conflict of interest.