Long-term efficacy of HDM-SCIT in pediatric and adult patients with allergic rhinitis

Allergic rhinitis (AR) is a global health problem with a prevalence of up to 50% in some countries [1]. AR affects the quality of life of approximately 250 million (17.6%) people in China and is associated with a substantial economic burden to society [2]. The prevalence of AR among students (10–17 years old) is as high as 42.5% (self-report) in Central China [3]. House dust mites (HDMs) are the most common aeroallergens in patients with perennial AR. The positive rate of HDM sensitisation in children with AR is 93.1% in Changsha, China [4]. HDM-induced AR is associated with a higher risk of asthma [5, 6], the prevalence of which is increasing in many countries, especially among children. Allergen-specific immunotherapy (AIT) is the only treatment that alters the natural course of AR and prevents asthma and other allergies by inducing immunotolerance [7, 8]. Subcutaneous immunotherapy (SCIT) has been the gold standard treatment, although sublingual immunotherapy (SLIT) has emerged as an effective and safe alternative. [9, 10]. According to a recent network meta-analysis-based comparison, the symptom score-based clinical efficacy of SCIT was higher than that of SLIT drop or tablet [11]. A cluster regimen, which reduces the dose-escalation phase from 14 to 6 weeks and reduces clinical visits by 53%, is a clinical practice that facilitates the treatment of patients with tight timetables. Comparative data for cluster SCIT and conventional SCIT showed similar efficacies [12‐15]. However, few studies have compared the long-term efficacy of cluster SCIT between children and adults. The present study aimed to evaluate the long-term efficacy of cluster HDM-SCIT in children and adults.

Although SCIT is a well-validated effective alternative for HDM-induced AR patients, it is less convenient compared with SLIT. A cluster schedule can reduce over half of the clinical visits in the updosing phase of SCIT and achieve a rapid increase in HDM-specific IgG, especially IgG4 [14], as well as an early response in clinical efficacy indicators [17]. Nevertheless, the safety risks should be taken into concern. The incidence of SADRs to SCIT was reported to vary between 0.06 and 1.01 per 100 injections [18], similar to the current study (0.68). The pediatric group showed a significantly higher risk of SADRs (1.26% per injection) compared with the adult group. However, it was lower than that reported in another study using a conventional schedule based on a pediatric population in China (4.6% per injection) [19]. LARDs are more frequent than SADRs, but are often well tolerated. Data reported by Nelson et al. showed that LADRs were experienced in 26–86% of injections [20]. The cluster schedule during the updosing phase did not influence the overall safety of the three-year SCIT compared to the previous studies using the conventional schedule.

The long-term efficacy of cluster SCIT has rarely been published, especially the direct comparison of long-term efficacy between children and adults using cluster SCIT. In this study, the minimal post-treatment follow-up duration was 3 years, and 48.45% (n = 78) patients were followed up for > 6 years after SCIT termination. The longest post-treatment follow-up period was 13 years (n = 6, three children and three adults). The TNSSs of patients who completed SCIT 13 years ago were still lower than that at baseline in the current study. A previous clinical study with a post-treatment follow-up period of 10 years (n = 20) reported no significant differences between the symptom scores obtained at three years and 10 years after HDM-specific SCIT treatment [21]. However, the sample size in this study was also limited. Another long-term follow-up study (n = 147) on patients (aged 16–25) with grass and/or birch pollen-induced AR reported improvements in rhinoconjunctivitis, and preventive effects of developing asthma of specific immunotherapy could persist for 7 years [22]. A large-scale evidence-based real-world study (n = 2350) of SCIT showed significant effects for up to 6 years (mean 3.4 years) in patients with AR, based on the number of AR medications and reductions in asthma [23]. Real-world evidence (RWE) data could reflect the efficacy of SCIT in practical applications rather than in various typical practice settings. Owing to the differences in medical service systems, reliable RWE is currently difficult to achieve in China.

To reflect the real-world application of SCIT, the severity of symptoms, use of medications, polysensitization, or a combination of asthma (controlled) were not serving as inclusion or exclusion criteria in the current study. The symptom scores, MS, and RQLQmini scores were all significantly lower in the pediatric group than those in the adult group, in line with the clinical practice. In both groups, TNSS improvements were moderately positively correlated with the baseline TNSS. This may explain the more significant TNSS improvements in the adult group compared with those in the pediatric group. Another study with a similar baseline TNSS conducted by our team revealed better improvements in children compared to adults [24]. The long-term efficacy (two-years post-SCIT) in children showed a slightly greater but not statistically significant (p = 0.905) improvement during the post-treatment years, compared to adults. However, in the current study, the improvement in TNSS post-treatment was more significant in the pediatric group than that in the adult group. To investigate the post-treatment effects of SCIT, a follow-up period > 3 years may be more valuable. The efficacy evaluation of SCIT in both the previous and current studies was based on subjective symptom scores, and the placebo effect is an issue to consider. The mean placebo effect in the SCIT trials with comparable allergen exposure (HDMs) ranged from 29.7% to 41% in the second treatment year and, in contrast, reached only 1% in the SLIT trial [25]. It has been reported that the perceived placebo effect was significantly more favorable in children than adults. [26] But in the current study, the adult group reported better TNSS improvements than the pediatric group after SCIT was completed, which the placebo effect cannot explain. O. Pfaar et al. [27] conducted a placebo-controlled study with an HDM allergoid SCIT in allergic rhinoconjunctivitis patients. They reported that after the first 6 months of treatment, a similar improvement was observed in both the treatment groups and in the placebo group, but at 12 months, a further decrease in the treatment group was observed while the decrease in the placebo group remained approximately the same. The same phenomenon was seen in several AIT studies [28, 29]. That means the placebo effect does have a significant limitation compared with the treatment effect induced by SCIT. In addition, longer follow-up duration was associated with a smaller placebo effect size [30]. The additional improvement in TNSS, after SCIT cessation, in the pediatric group may have no relationship with the placebo effect. A 10-year follow-up cohort study showed persistent improvements in rhinoconjunctivitis and the potential to prevent asthma development in children with AR for up to seven years. [31] The effect of slowing asthma progression is more pronounced in children than in adults [32]. The different long-term benefits suggest that the influence of immunotherapy on allergic symptoms may vary in adults and children. The HDM-SCIT responsiveness was independent of the allergic pattern in the pediatric and adult groups in the current study. The result was consistent with the previous findings of Song et al. who found that single-allergen SCIT is beneficial for treating AR caused by multiple allergens in pediatric populations [33].

This is the first study to report that TNSS may continuously improve beyond immunotherapy termination in children who complete a three-year SCIT during childhood. The baseline TNSS in the pediatric group was negatively correlated with post-treatment benefits. Furthermore, 86.4% of non-responders in the pediatric group showed further improvement in TNSS during the post-treatment follow-up. Regarding the influence of pharmacotherapy, CSMS improved in 17(77.3%) pediatric AR patients after the termination of SCIT. In our previous study, patients with a history of AR < 10 years maintained better HDM-SCIT efficacy during post-treatment (two-year) observation [24]. Children who completed SCIT during childhood with a low baseline TNSS may gain additional benefits later. The mechanisms of AIT are still not fully understood. Tolerance is accompanied by Th1/Th2 rebalancing, changes in secretory cytokines, production of IgG4 isotype allergen-specific blocking antibodies, induction of regulatory subsets of T and B cells (Tregs and Bregs), and a decrease in inflammatory responses to allergens by effector cells (mast cells, basophils, and eosinophils) and upstream dendritic cells (DCs) in inflamed tissues [33]. The reported mechanism studies of AIT were mostly based on adult populations. The immune systems of children are not fully matured. The impact of immunotherapy on allergic diseases in children may more profound. The mechanism of the long-term efficacy achieved with AIT in children merits further study.

The current study has some limitations. Post-treatment dropouts were relatively high. The limited sample size did not enable further stratified analysis of patients with different post-treatment follow-up durations. As blood samples were not collected, evaluation of biomarkers in patients with different responsiveness and long-term outcomes was not possible.

Children and adults with HDM-induced perennial AR achieved sustainable efficacy of a three-year SCIT for at least 3 years (up to 13 years) after treatment. Patients with relatively severe nasal symptoms may show more significant improvement after treatment. Children who complete a full course of SCIT in childhood may gain further improvement after SCIT cessation, regardless of the responses immediately after the immunotherapy.