Social and economic costs of allergic rhinitis (AR) are relevant as AR may significantly impact school attendance and performance, quality of life, sleep, and is associated with many comorbidities, including asthma and respiratory infections (RI) [12].

The AR immunopathology is characterized by T helper 2 (Th2)-dependent inflammation and Th1-response impairment. This imbalance is sustained by dysfunction of immune system: allergic patients have a functional defect of allergen-specific T regulatory cells, so Th2 cells may polarize the immune response to allergen and produce large quantity of some interleukins, including interleukin (IL) 4, IL-5, and IL-13, that in turn promote IgE synthesis and eosinophil production, recruitment, and activation at nasal level. Th2-cytokines up-regulate the endothelial and epithelial expression of adhesion molecules (such as intercellular adhesion molecule [ICAM-1]), which interact with other adhesion molecules (e.g., leukocyte functional adhesion-1 expressed by leukocytes) to induce the mucosal infiltration by eosinophil. In addition, involvement of other T helper subsets, namely Th17 and Th9, has been reported. Severity of AR may be associated with increased levels of IL-17 and IL-9. This complex pathogenesis highlights the relevant impairment of immune response in AR. In addition, Th2-, Th1-, and Th9-dependent cytokines are involved in inflammatory events. Therefore, allergic inflammation represents the main characteristic of AR.

It is strengthened belief that allergic patients could present higher susceptibility to contract RI than nonallergic subjects. In this regard, it has been evidenced that allergic children have more numerous and severe RI than nonallergic children [3]. The involved pathways may be: (1) impaired immune defence because of interferon (IFN)-γ defective production, consequent to Th2-polarization [45], (2) overexpression of ICAM-1 (the main rhinovirus receptor) depending on allergen exposure, (3) augmented mucus production together with impaired mucus consistency, and (4) persistent mucosal inflammation as pabulum for microbes overgrowth [56]. In addition, it is well known that AR is a main risk for asthma [7], both concerning the onset and the worsening [8]. In other words, allergic reaction may be considered the promoter of different sequential steps: (1) allergen exposure induces expression of adhesion molecules, (2) so allergic inflammation flares, (3) symptoms occur, (4) overexpression of ICAM-1 favours viral adherence, (5) RI cause asthma attack. Therefore, adequate control of allergic inflammation in AR patients is important as it induces symptom relief and could prevent infections recurrence [9]. In this regard, allergen immunotherapy (AIT) may restore a physiological immune and clinical tolerance to the causal allergen and exert anti-inflammatory effects, mainly concerning a fast increase of IFN-γ production after AIT [1011]. In addition, it has been reported that sublingual immunotherapy (SLIT) may reduce the number of RI in children with AR [12]. Children treated with SLIT actually had less allergic symptoms than control children as well as they had significantly less sore throat, headache, productive cough, and antibiotic use than children treated with medications alone [12]. In this regard, it may be hypothesized that these beneficial effects might be based on a restored physiological Th1-polarization and a damping of allergic inflammation [13].

House dust mite (HDM) sensitization is very frequent in childhood and is characterized by a persistence of Th2-dependent allergic inflammation [14]. Therefore, the present preliminary study investigated whether six-month SLIT at high dose may reduce the number of RI in HDM allergic children.

We assessed 40 paediatric patients (18 males; mean age, 9.3 ± 1.8 years), 20 undergoing symptomatic drugs alone (group 1) and 20 treated by SLIT (group 2).

The two groups were well matched concerning age, gender, AR severity, RI episodes in the previous year, as reported in Table 1.

The total number of infections was significantly different in the two groups: Group 1 had more (p < 0.05) RI episodes (5.45) than SLIT group (3.5) (Fig. 1). In particular, the number of pharyngo-tonsillitis episodes was minor (p < 0.05) in SLIT-treated patients (Fig. 2A) as well as the bronchitis episodes was significantly minor (p < 0.05) in group 2 (Fig. 2B). Snoring was significantly (p < 0.05) reduced in SLIT group in comparison with control group as shown in Fig. 2C. About fever, 18 children treated with medications alone had fever, whereas only 8 SLIT-treated children had fever (p < 0.01), as shown in Fig. 2D. On the other hand, there was no difference about the number of common colds episodes in the two groups: 3.1 in control group and 2.2 in SLIT group.

SLIT-treated children took significantly less antibiotics (p < 0.05) and fever-reducers (p < 0.01) than control group (Fig. 3).

Th2-dependent inflammation is the hallmark of AR. Allergic inflammation promotes frequent RI episodes. Previously, it has been evidenced that allergic patients have a two-fold increase of RI risk, and duration almost 3 weeks longer of the symptoms than in nonallergic subjects [16]. In addition, it has been demonstrated that rhinovirus-induced infection in atopic subjects heightened susceptibility to the detrimental effects of colds both concerning immunological and clinical aspects [17]. Another study reported that atopic asthmatics suffer from more frequent lower-respiratory-tract infections and have more severe and persistent lower-respiratory-tract symptoms than normal subjects [18]. Thus, a relevant link between RI and AR exists as underlined by several studies [1920212223242526]

Allergen-specific immunotherapy exerts profound effects on immune response, mainly concerning the balance between Th1 and Th2 cells. Particularly, immunotherapy induces an increased IFN-γ production [27]. Therefore, this study aimed at evaluating whether high-dose SLIT may affect RI in children with AR due to HDM sensitization.

Effectively, SLIT-treated patients showed a significant reduction of the total number of RI, associated with diminished use of both antibiotics and fever-reducers in comparison with drug-treated patients. A possible explanation of this relevant effect might be due to the modulation of Th2-polarized immune response in SLIT-treated patients. Indeed, it has been evidenced that SLIT was able of both increasing IFN-γ production and reducing allergic inflammation, assessed by the biomarker soluble HLA-G [28].

The present study confirms a previous multicentre real-life study that evidenced the SLIT ability in exerting "extra antiallergic" effects, mainly concerning RI [12]. Therefore, there is evidence that SLIT is an effective a safe route of AIT [2930] and may have additional activity as provided by preliminary studies, including this preliminary experience.

However, the present study should be considered preliminary because it has some main limitations: it was an open study, recruiting a relatively restricted number of patients; cytokines, chemokines, and mediators, including adhesion molecules, were not evaluated; the SLIT treatment duration was short (6 months) as well as the clinical observation period was short. We decided to design this short course because it is well known that AIT is a long-term treatment, but this involves a relevant drawback: an inadequate adherence to AIT. Thus, the perception of achieving clinically relevant outcome, such an impact on RI, could reinforce the awareness of AIT efficacy. We have to consider another important limitation: the absence of cultural, viral or bacterial, determination. In addition, as RI are more common in younger children, such as from 3 to 6 years old, the present study in children aged 7 onward gives preliminary and partial information. Therefore, this preliminary experience should be confirmed by controlled and lab-based trials recruiting larger cohorts, mainly enrolling younger children (<6 years) and considering longer SLIT treatment and observation time.

Additionally, it is to consider that also omalizumab administration was able to eliminate spring and fall asthma exacerbations [31], which are primarily caused by viral RI [32].

In conclusion, AR should be adequately treated, mainly concerning the comorbidities, including RI, as its impact on social and economic aspects is relevant. This preliminary study might suggest that also a short course (6 months) of high-dose SLIT, titrated in µg of major allergens, could reduce RI in allergic children.