Efficacy of Pidotimod use in treating allergic rhinitis in a pediatric population

Chronic nasal obstruction is an underestimated condition that severely affects the quality of life of many patients, by impairing sleep quality. The resulting irritability and chronic fatigue reduce  cognitive function and school performance over time [1].

Allergic rhinitis (AR) and adenoidal hypertrophy (AH) are the most frequent causative disorders of nasal obstruction in children, leading to recurrent respiratory infections (RRI) and contributing to the development of rhinosinusitis and obstructive sleep apnea (OSA) [2].

The prevalence of AR has been estimated to be approximately 2 to 25% in children, depending on age. The chronic allergic inflammation of nasal mucosa is responsible for nasal discharge, itching, sneezing, blockage or severe congestion, but also for recurrent infections [3]. The peculiar cytokinic storm of allergic inflammation leads to an impairment of natural immunity with a reduced expression of Toll like receptors (TLRs) and a decrease of ɣInterferon (ɣ-IFN) production. This impairment is responsible for prolonged viral survival and increased viral replication, explaining why allergic children are more susceptible to Respiratory Syncytial Virus (RSV) and Rhinovirus (RV) infections [4]. Indeed, the target therapy of allergic diseases is allergy immunotherapy (AIT) with a desensitizing effect that not only causes improvement of allergic symptoms but also a significant reduction in RRI [5].

Also AH is very common in pre-school children, often associated with recurrent inflammation of upper airways and allergic diseases. Clinical features, due to nasal obstruction, include mouth breathing, snoring, hyponasal speech and adenoid facies. However AH is a dynamic and potentially reversible condition under medical therapy but chronic infections, either viral or bacterial, can keep the pad of adenoids enlarged for years [6].

How and if this susceptibility could be due to the microbiota of the nasal mucosa is still controversial. Nasal cavities are the less investigated ecosystem and only recently extensively studied, showing that are often colonized by a temporally stable microbial community susceptible to environmental changes [7].

Actinobacteria, mainly Propionibacterium and Corynebacterium spp., and phylum of Firmicutes, in particular by the genus Staphylococcus spp., are the predominant species. Among them, Staphylococcus aureus seems to play a major role, affecting the composition of the microbiota with its presence and proportion [8]. Furthermore, nasal microbiota holds a large number and variety of viruses, especially in preschool age children with upper respiratory tract infections (URTI). Susceptibility to URTI is para physiological in the first years of life and is due to the slow and incomplete maturation of the immune system.

Several strategies that involve the use of immunomodulators or pre-probiotics had been proposed, with encouraging results. The efficacy of immunomodulators could be due to the direct action on the mechanisms of natural and adaptive immunity [9]. As for probiotics, modifications of the microbiota due to the addition of selected bacteria could induce a virtuous cross-talking between the microbiota itself and the immune system, with a better clearance of pathogens.

Although AR and AH present a different etiopathogenesis, they have in common a minimal chronic inflammation surrounding nasal obstruction; hence it would be challenging to evaluate the effect of an immunomodulator on this minimal chronic inflammation with possible clinical and microbiological effects .

Therefore the aim of this study is to evaluate Pidotimod efficacy on nasal obstruction in children with AR and/or AH and whether its action involves a variation of nasal microbiota.

Out of 76 children enrolled, a total of 70 complete the follow up and entered the study: 41 male (58.6%) and 29 female (41.4%) aging from 6 to 12 years (mean age 8.61 ± 1.87).

We reported 6 drop-out (between 9 and 12 years of age): 5 among controls and 1 in AR group, mostly due to a low family compliance; no any adverse event was recorded.

57 children presented nasal obstruction: 26 children with AR, 16 with AH and 15 with AR + AH. The remaining 13 children were considered as CTRL. No differences were observed concerning the distribution of age and sex between all the groups.

All the children enrolled (57 in treatment with Pidotimod and 13 controls) performed a second visit (T1) after 30 days (+/− 7 days).

This is the first study that evaluates the functional effects of Pidotimod on nasal obstruction in children with AR or AH.

Our data shows that the administration of Pidotimod is able to improve nasal flow significantly in few weeks and that this effect is not mediated by variations in the nasal microflora but it could be due to an inflammation decrease. The composition and prevalence of the species considered does not differ significantly either among children with AH, AR and AR + AH or CTRL.

This data differs from recent observations suggesting that nasal microbial composition is linked to a specific clinical situation, such as AR [18].

However, it should be noted that results derived from various studies are not comparable because in the majority of them the target population consisted of adult subjects, with asthma or rhinosinusitis [19‐21]. Moreover in all these studies, setting, case selection, sites and methods of sample collection were disparate. In fact, to date and to our knowledge, pediatric studies are relatively few and heterogeneous. Teo et al. studied microbioma of nasopharyngeal aspirates across the birth cohort of the CAS study, providing a characterization of bacterial communities within the human nasopharyngeal microbiome during the first year of life [22]. They found that early asymptomatic Streptococcus colonization at 2 months of age was significantly associated with chronic wheezing at 5 years of age, as consequence of a younger age of first lower respiratory infection (LRI). The antibiotic use disrupted asymptomatic colonization patterns leading to an increased risk of LRI and later asthma development. Our results, instead, refer to children of different ages, preschool and school age, where the microbiological profile has been strongly influenced by prolonged environmental stimuli. Given the physiological susceptibility to infections, it is not surprising that nasal microflora is heterogeneous with marginal differences between atopic and non atopic children at this age.

Similarly, Cardenas et al., identified a higher frequency of potential pathogens (Haemophilus, OR  =  2.12; Staphylococcus spp, OR  =  124) in oropharyngeal swabs samples of wheezy infants compared to controls [23]. Authors speculate that these bacteria might contribute to a wheezy diathesis in infants and to asthma later in life.

Since all children treated with Pidotimod demonstrate a measurable and significant reduction in nasal obstruction regardless of the underlying disease and without significant changes in the microbiota, this effect appears likely to be due to the direct action of Pidotimod on the immune response.

Pidotimod has shown an excellent profile of tolerability and safety in addition to a significant effectiveness in modulating immune response and in controlling RRI [24‐26]. In vivo and in vitro studies showed that Pidotimod could improve immune response, affecting both adaptive both innate immunity. It is able to induce dendritic cells (DCs) maturation with the release of cytokines and other pro-inflammatory molecules, driving T-cells proliferation and differentiation towards a Th1 phenotype [27‐29]. Furthermore, as shown in an ex-vivo study, Pidotimod could modulate the airway epithelial cells functions, up-regulating the expression of toll-like receptor-2 (TLR-2) on their surface which is known to recognize many bacteria, fungi and viruses [27].

Esposito et al., studying 20 children with community acquired pneumonia, demonstrated that Pidotimod administration in addition to standard antibiotic therapy might increase the natural immune response to an infectious stimulus, implementing maturation and function of the DCs [30]. We have indirectly observed an analogous rapid effect of Pidotimod in the analysis of intragroup differences in response to the therapy. After only 1 month, AR children have a significantly better nasal flow than AH children (with or without atopy) suggesting that this is due to its immunological action. Where in fact there is also an anatomical obstructive component, as in AH, the response is lower, because the resolution of the hypertrophy could be slower. However, it is possible that a specific antiallergic activity of the Pidotimod may also contribute to these results. In 2001 Gourgiotis et al. reported that Pidotimod induced in vitro a decrease in the expression of CD30 on peripheral blood mononuclear cells (PBMN) of atopic children [31]. More recently, Zhai et al. conducted a study on 60 children with asthma and AR treated with allergy immunotherapy (AIT), in which the study population was randomized for an additional treatment with Pidotimod. Children that received Pidotimod in addition to AIT, showed an improvement in the immunological parameters and in the respiratory function in respect to the controls. Therefore, it was supposed that Pidotimod was able to affect the Th1/Th2 balance and to have an anti-allergic role [32].

Our pilot study confirms that Pidotimod has a clinical and measurable effect on the stimulation of the immune system in children with inflammation and nasal obstruction, more evident in allergic subjects. The limits of our study consist above all in the number of cases and in the short time of observation. It is therefore conceivable that the prolongation of Pidotimod therapy in children with AH could lead to an obviously slow and progressive reduction. We did not clinically evaluate the intercurrent episodes and did not investigate the immunological studies.

However, we have considered nasal obstruction as a surrogate of an inflammatory condition and a susceptibility to RRI.

The strength of our study on one side is the choice of the sample population that allowed us to compare different types of inflammation and on the other side the study of parameters, such as the nasal flow, which is measurable and not operator-dependent.

In this prospective the discrepancy between objective results, such as the nasal flow, and the subjective ones like the NSS, confirm the importance of this detection. As we have previously shown, children underestimate the nasal obstruction and are unable to give a true measurement of their symptoms [33].

This pilot study demonstrates for the first time that the use of an immunomodulatory molecule such as Pidotimod is able to give a rapid improvement on nasal obstruction, especially in AR children. This effect seems to be not mediated by consistent changes in nasal microbiota, so further studies are recommended to investigate the underlying immunological and microbiological mechanisms.