Safety of house dust mite subcutaneous immunotherapy in preschool children with respiratory allergic diseases

Allergen immunotherapy (AIT) can induce immune tolerance to allergens and has a disease-modifying effect for immunoglobulin E (IgE)-mediated allergic diseases [1, 2]. When allergen extracts are administered, immune responses are elicited, including the activation of specific blocking antibodies (eg. IgG4), tolerance-inducing cells (eg. regulatory T and B cells), and mediators (eg.cytokines including IL-10 and TGF-β) [1]. These responses prevent further exacerbation of the allergen-triggered immune response and attenuate the inflammatory response in tissues [1, 3]. AIT also appears to have a long-term clinical efficacy of up to 12 years even after treatment cessation [4]. In addition, AIT prevents the development of asthma and hypersensitivity to novel allergens [5]. As AIT is the only causal treatment for IgE-mediated allergy, the World Allergy Organization (WAO) recommend AIT can be considered as initial treatment and failure of pharmacotherapy is not an essential prerequisite of the use of AIT [6]. For respiratory allergy, AIT may be proposed as an early treatment in the therapeutic strategy [1, 6]. However, in several AIT guidelines [1, 6], the lower age limit for children eligible for this treatment is set at 5 probably for concerns that children under 5 show less cooperation and limited ability to report the early signs and symptoms of severe allergic side-effects in the age. These concerns are understandable but not necessarily well-supported by evidence.

It is well known that natural history or typical progression of allergic diseases (namely allergy march) such as atopic dermatitis, food allergy, allergic rhinitis (AR) and asthma often begin early in life, while AIT is the only treatment that may alter the progression of allergic diseases [7, 8], the decision of initial AIT in age below 5 years old group always depends on how to balance the benefit of early intervention and risk of potential side effects. For safety concerns, children under 5 have been listed in the EAACI guideline as a relative contraindication of AIT, both in sublingual immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT). However, some studies had shown that SLIT in children below 5 years old were effective and there was no difference in the safety profile in this age group and older children. One study included children aged 2–5 years receiving SLIT for house dust mite (HDM) allergy, only mild-to-moderate local adverse reactions were reported [9]. For SCIT, there have been reported a relative higher risk of side effects including local reactions (LRs) and systemic reactions (SRs) than SLIT. In SCIT trials, SRs occurred in 6–17% of pediatric asthma patients [10], grade 1 reactions were the most frequent in both adults and children [11]. There are limited studies of SCIT in under-five age group. A retrospective study of SCIT in 239 children below the age of 5 years (8–59 months old), who received a total of 6689 injections, reported a single systemic reaction 90 min after an injection in a 3-year-old boy [12]. According to current data, adverse effects of AIT were not more frequent or more severe in children below 5 years old group.

HDM is one of the most common sources of indoor allergens and can trigger perennial AR, asthma. Our previous study found that HDMs were the major aeroallergens among AR patients in central China, with a sensitization rate of over 90%. In the confirmed AR children below 6 years old, the sensitization rate of HDM [including Dermatophagoides farina (Df) and Dermatophagoides pteronyssinus (Dp)] was 97.6% [13]. SCIT with commercial HDM extracts of Dp (Alutard SQ, ALK Hørsholm, Denmark) have been demonstrated to be effective in children with AR and/or asthma [14‐16]. This study aimed to investigate the incidence of side effects and potential risk factors during HDM SCIT in preschool children with respiratory allergy.

Allergen immunotherapy in preschool children is always a dilemma for the physicians. On the one hand, there are strong evidences to support early introduction of AIT to prevent allergy march [7, 8]; on the other hand, younger children always show stronger resistance to AIT and cannot depict their symptoms accurately when adverse reactions happen. Moreover, they have often upper respiratory infections resembling allergic symptoms. Recently some studies suggested SLIT was rarely associated with moderate or severe SRs and SLIT was considered to be safe in children younger than 5 years old [23, 24]. However, due to the limited studies of SCIT and SLIT in under-five age group, most guidelines have no recommendation of AIT in this population. In our study, we investigated the safety profile of the HDM SCIT in preschool children by examining the incidence of LRs and SRs with conventional SCIT regimen. We found that the HDM SCIT could be considered safe in preschool children with respiratory allergic diseases. In addition, during maintenance phase one subcutaneous injection per month was adequate in order to maintain efficacy of SCIT.

The immediate LRs in preschool patients were common in our study. Nearly 70% of our patients experienced immediate LRs during SCIT. It is easy to understand that the majority of LRs happened in high dosage HDM extracts (No.4 vial) injection. The incidence of immediate LRs in preschool patients was similar to that observed in patients aged 5–60 years in our previous study [15]. This suggests that SCIT in age below 5 years old group is as tolerable as for children aged above 5 and adults. Some reports showed that up to 93% of patients experienced immediate LRs during SCIT [10, 25, 26]. The differences of immediate LRs rates may be due to the allergen type and allergen extracts used in different studies. For example, pollen extracts and depot allergen extracts were easier to evoke LRs than HDM and aqueous allergen extracts [27]. The HDM vaccine we used in our study were Al (OH)3 absorbed sustain-released extracts, which may lead to a relatively high incidence of LRs. Interestingly, the delayed LRs appeared less than those in other studies, it might be related to the knowledge and judgment of the parents, as the delayed LRs were usually recorded in home, sometimes the delayed LRs records were missing. Risk factors analysis showed that children with high specific IgE level and high BMI were prone to develop LRs. We speculate this might be due to that the adipose tissue limited the diffusion of allergen extracts in high BMI children. However, this finding needs to be validated in larger population. Since LRs usually disappeared in a period ranging from several hours to 3 days and didn’t need any medical intervention in most cases, the attempt to reduce LRs by dosage adjustment may not be necessary in this population, unless large LRs happens and the LRs become intolerable.

We found the incidence of immediate and delayed SRs in the preschool patients was similar to that previously reported in children [28‐30], 12.09% of the population experienced SRs during SCIT. In some Chinese patients’ studies, SRs occurred in 12.26–18.49% of patients and 0.72–3.28% of injections in children. We also found the majority of the SRs were grade 1 and grade 2 reactions, which was consistent with previous studies [31, 32]. Only 2 /91 (4.55%) patients experienced grade 3 reactions within 30 min after injection and responded well to rescue medication, no patient had grade 4 or grade 5 reaction. These indicated that SCIT in age below 5 years old was as safe as in older children. Indeed, to assure the safety of these patients, we took an extra procedure that all the patients—including AR patients— to finish the PEF test before each injection. One challenge was that the younger children might not get the PEF value accurately. Thus, we didn’t expect the accuracy but require the good repeatability of the data. These mutually-confirmed data obtained from mini-PEF flowmetry and portable spirometry were utilized to ensure the eligibility to receive allergen injection. The preschool patients would postpone their injection if the PEF value didn’t achieve 80% of their predict value (or personal best value), which might be helpful to reduce the incidence of SRs in this population. Despite the extra step we had taken in our study, we still found the incidence of SRs were slightly higher than those in adolescents or adults (0.31–1.47% of injections, 5.68–10.98% of patients) [14, 30]. Another study also showed that the incidence of side effects was higher in the preschool (2 to 6 years old) group than the older (7 to 18 years old) group [33]. Considering that the majority of SRs happened in high dose allergen injection (usually Vial No.4) and the preschool children shared the same treatment regimen with the adolescents and adults, the maximum tolerable dosage in this population needs to be further investigated to make the balance between efficacy and safety. The dose of HDM extracts would be appropriately reduced after SRs if SCIT was continued, we usually reduced the dose to one that was previously tolerated or an even lower dose if the reaction was severe [34].

We found that LRs showed a correlation to SRs, but this correlation was not confirmed in the multivariable logistic regression analysis. Indeed, the correlation between LRs and SRs is still in controversy. Previous studies indicate that individual local reactions do not appear to be predictive of subsequent SRs. However, some patients with a greater frequency of large LRs might be at an increased risk of future SRs [34]. In our study, the children with large LRs would reduce their allergen dosage in the next injection as Cox et al. suggested [34], which might help to decrease the risk of SRs. Asthma (especially moderate asthma) has been identified as a risk factor for SRs in many studies [14, 35, 36]. However, asthma was not a risk factor for SRs in our population, which might be attributed to the fact that all of the 11 asthmatic children have mild asthma, and also the standardized pre-treatment evaluation procedure and careful allergen-dose adjustment during SCIT, as more than 1/4 of our preschool patients didn’t reach the recommended maintenance dosage (100,000 SQ) for adolescents and adults. We also found other variables including age and disease duration had no correlation with SRs. In other words, the SRs sounds to be unpredictable in the preschool patients, we need to be very caution for each injection to recognize the early signs of SRs in time.

Some limitations hampered our study. Firstly, we did not have placebo group (only contain adjuvant) and older-age group serveing as control group. Thus, this study was meant to be regarded as a descriptive research and the safety profile in this study needs to be interpreted with caution. Secondly, it is quite challenge to acquire the accurate value of PEF and FEV1 in these younger-age population. For this reason, we couldn’t present the lung function data in the results as evidence of SCIT efficacy. Instead, we listed this step as a part of pre-injection procedure in the SCIT. Finally, the number of children with asthma (11/91) was small in our study, which might lead to bias and made it difficult to evaluate the correlation between asthma and SCIT-related adverse reactions. More asthma cases are needed in further studies to figure out the relationship between asthma and SCIT safety in the preschool children.

Our study demonstrates that HDM SCIT is considered to be safe in preschool children with respiratory allergic diseases. The incidence of SRs is low and the severity of SRs ranges from mild to moderate in the preschool patients. LRs and SRs usually happen when high dosage allergen vaccine is administrated. Children with higher BMI and HDM sIgE level are prone to develop LRs. A comprehensive pre-treatment evaluation and careful allergen-dosage adjustment help to decrease the side effects of HDM SCIT in the preschool children.