Small airways in children with allergic rhinoconjunctivitis: the potential role of a multicomponent nutraceutical

Abstract

Allergic rhinitis and asthma are closely linked. A progression from rhinitis to overt asthma is common. FEF_25-75 is a spirometry parameter that could reflect small airways patency and could reliably predict early bronchial involvement in allergic rhinitis patients. MEF₅₀ very strongly correlates with FEF_25-75. The aim of this study was to evaluate possible spirometry change in two groups of children suffering from AR over time. The first group took a course of a nutraceutical (Lertal®) before the observation (active group, AG); a second one was considered as control (control group, CG). The children were visited at baseline, at the end of the nutraceutical course, and after 1 year. FEV₁, FVC, and MEF₅₀ were the primary outcomes. After one year, children in AG had significantly higher MEF₅₀ than CG children (p=0.009). In conclusion, the present study showed that a course with a multicomponent nutraceutical could prevent the MEF₅₀ decline in children with allergic rhinoconjunctivitis. (www.actabiomedica.it)

Introduction

Allergic rhinitis (AR) is a relevant risk factor for the development of asthma in children and is an important trigger factor for exacerbations in patients with asthma (1). Moreover, AR and asthma are closely associated both from a pathophysiological and a clinical point of view (2). AR frequently may precede asthma insomuch as it has been proposed the term “asthma march” to define the progression from AR towards asthma (3). In this regard, a functional link has been described between nasal airflow and bronchial airflow (4,5). Alike, there is a close association between allergic inflammation and nasal obstruction (6,7). These concepts support the unbreakable relationship between the upper and lower airways, in health as well as in disease. Although upper and lower airways diseases share the same pathophysiological features, their management and treatment are commonly applied in an undesirable and independent manner, counteracting the concept of unified airways observed several years ago (8).

The increase of allergic rhinitis (AR) comorbidity in patients with asthma is consistent with the increase of asthma comorbidity in subjects with AR (8). AR is one of the most frequently reported asthma comorbid conditions (9). Moreover, AR appears to be a negative early-life predictive factor for an accelerated decline in lung function. Interestingly, a persistent, severe and protracted history of AR is associated both with a major airway dysfunction and with a severe asthma phenotype (6). In this regard, small airways are early impaired in AR patients and a pathological value of the forced expiratory flow between the 25% and 75% of the vital capacity (FEF_25-75), such as <65% of predicted, could be a reliable marker of subclinical asthma (11). Actually, FEF_25-75 has been considered also a surrogate marker to investigate small airways (12).

Taking account these concepts, lung function testing should be performed in patients with AR to early detect bronchial impairment. The gold standard parameter to define bronchial obstruction in asthma is the forced expiratory volume in one second (FEV₁), even though it may be normal during symptom-free periods (13). In this situation, FEF_25-75 could be fruitfully considered (14). FEF_25-75 correlates very well with another spirometry parameter: the maximal mid expiratory flow rate at 50% of vital capacity (MEF₅₀) as elegantly demonstrated (15). Equally, MEF₅₀ provided a diagnostic and prognostic utility in clinical practice (16).

Notably, it has been reported that the progression from AR to asthma could be prevented by appropriate treatments, including allergen immunotherapy (17). In this regard, Lertal® is an oral food supplement, containing: Perilla frutescens 80 mg (as dry extract), Quercetin 150 mg, and Vitamin D₃ 5 mcg (200 IU). It exerts anti-allergic and anti-inflammatory activity that may be fruitful in reducing and preventing AR exacerbation as recently evidenced by a randomized controlled study (18,19).

On the basis of this background, the current study aimed at evaluating the carry-over effect of a Lertal® course (lasting 2-4 months) on lung function testing, mainly concerning MEF₅₀, in children with AR in one year.

Materials and Methods

Globally, 53 patients with allergic rhinitis were evaluated retrospectively.

Allergic rhinitis was diagnosed according to validated criteria, such as on the consistency between history and sensitization (1). These children belonged to a cohort included in a randomized, polycentric, double-blinded, parallel-group, placebo-controlled trial held in two phases (18.19).

Inclusion criteria were: age range 6-12 years, AR diagnosis, sensitization to house dust mites or pollens, Total Symptoms Score (TSS) ≥ 15 and at least 1 for nasal congestion, written informed consent of patients and of parents or legal guardians. Exclusion criteria were: uncontrolled asthma, secondary rhinitis to other causes, concomitant acute or chronic rhinosinusitis, nasal polyps, current use of topical or systemic corticosteroids, antihistamines, antileukotrienes, inadequate washout of them, nasal anatomic defect, respiratory infections in the last 2 weeks, participation in other clinical studies in the last month, documented hypersensitivity to the study product or its excipients, and trip planned outside of the study area.

After 2-week run-in period, eligible patients were randomly (1:1 ratio) treated with Lertal® double-layer tablets (1 tab/day for 4 weeks) plus standard therapy or Lertal® placebo tablets (1 tab/day for 4 weeks) plus standard therapy: phase I. As Lertal® was considered as add-on treatment, the standard therapy was continuous antihistaminic treatment. Systemic or intranasal corticosteroids, leukotriene antagonists, and sodium cromoglicate were prohibited during the study.

The phase II was an open-label, parallel-group, extension study in which patients treated with study product in Period I continued treatment with Lertal® tablets, whereas patients initially treated with placebo received no further treatment. After the 4-week active treatment period, children treated with Lertal® plus standard therapy continued to take Lertal® tablets (1 tab/day for 4-12 weeks) alone (such as without antihistamines), whereas children treated with Placebo suspended any treatment. The current treatment lasted 4 weeks in children with pollen allergy, whereas 12 weeks in children with perennial allergy.

The duration of Lertal® treatment lasted 8 (in children with pollen allergy) or 16 weeks (in children with mite allergy) overall.

At the end of the trial, some children were observed for one year. During this one, children were treated with antihistamines on demand.

The children were visited at the enrolment, at the end of the trial, and after one year, a spirometry was performed during each visit. Three main parameters were evaluated: FEV₁, FVC, and MEF₅₀. They were considered as percentage of predicted according with International guidelines (20).

Continuous data were summarized by means of common descriptive statistics: mean, standard deviation (SD), median, first and third quartiles, minimum and maximum. Categorical data were presented by absolute and relative frequencies (n and %) or contingency tables.

Demographics characteristics (i.e. age, sex and type of allergy) were summarized overall and by treatment by means of summary descriptive statistics.

FEV₁, FVC, and MEF₅₀ values were summarized overall and by treatment by medians of summary descriptive statistics considering the overall population. Spirometry parameters were graphically represented by means of box plots by treatment in the overall population considering the medians and the interquartile range (IQR).

The between-group analyses were performed considering the overall population by means of t-test for independent samples or analogous non-parametric test (i.e. Wilcoxon rank-sum test in case of non-normal distribution of data assessed by Saphiro Wilk test).

Results

The demographic characteristics of the children are reported in Table 1. The mean age was 9.42 ± 1.97 years. There were 35 males. Thirty-three children had pollen allergy and 20 had mite allergy.

Table 1.

Demographic characteristics of the subjects. Data are express as absolute numbers, mean, and standard deviation

	Active Group	Control Group	Total
Number of subjects	28	25	53
Age (years)	9.46 ± 2.05	9.36 ± 1.91	9.42 ± 1.97
Males	20	15	35
Females	8	10	18
Pollen Allergy	19	14	33
Mite Allergy	9	11	20

There was no significant difference between groups at baseline.

FEV₁

The median value was 94 (IQR 90-97.5) in the active group and 93 (IQR 89-75) in the control group at the enrolment. The median value was 95 (IQR 92-97) in the active group and 94 (IQR 93-96) in the control group at the end of the trial. The median value was 96 (IQR 94-99) in the active group and 93 (IQR 88-95) in the control group at on year (Figure 1).

Figure 1.

Box-plot of the FEV₁ values (expressed as % of predicted) in active group (grey) and control group (white) at the enrolment, at the end of the trial, and at one year. Data are expressed as medians, IQR, and minimum and maximum values

FVC

The median value was 94 (IQR 92-97.5) in the active group and 95 (IQR 90-97) in the control group at the enrolment. The median value was 96 (IQR 93-99) in the active group and 96 (IQR 92-98) in the control group at the end of the trial. The median value was 96.5 (IQR 93.5-99) in the active group and 94 (IQR 91-97) in the control group at on year (Figure 2).

Figure 2.

Box-plot of the FVC values (expressed as % of predicted) in active group (grey) and control group (white) at the enrolment, at the end of the trial, and at one year. Data are expressed as medians, IQR, and minimum and maximum values

MEF₅₀

The median value was 85 (IQR 83-88) in the active group and 85 (IQR 83-87) in the control group at the enrolment. The median value was 87 (IQR 85-88.5) in the active group and 87 (IQR 85-89) in the control group at the end of the trial. The median value was 88.5 (IQR 85.5-90.5) in the active group and 84 (IQR 82-87) in the control group at on year (Figure 3).

Figure 3.

Box-plot of the MEF₅₀ values (expressed as % of predicted) in active group (grey) and control group (white) at the enrolment, at the end of the trial, and at one year. Data are expressed as medians, IQR, and minimum and maximum values

The intergroup analysis showed that there was no significant difference between group at any time about FEV₁ and FVC.

There was significant difference between groups at one year for MEF₅₀ (p=0.009).

These outcomes were confirmed after stratification for pollen or mite allergy (data not shown).

Discussion

FEF_25-75, as well as MEF₅₀, deserves an adequate and careful consideration in patients with asthma and/or allergic rhinitis as well as in the general population because low values can add fruitful information about asthma, rhinitis, and allergy in the common practice.

Many attempts were tried to prevent the progression from allergic rhinitis toward asthma, including pharmacological and immunological treatments.

Nutraceuticals are a wide class of compounds that consists of herbal medicine, probiotics, and vitamins. Many of these components exert clinically relevant effects and the literature reports evidence of beneficial properties (21).

The current study demonstrated that a course of a multicomponent nutraceutical, i.e. Lertal®, lasting 8 or 16 weeks, exerted a carry-over effect on MEF₅₀ within one year. MEF₅₀ is a spirometry parameter that substantially corresponds to the most popular FEF_25-75 as ery strongly correlates with it (15).

Even though the difference between the groups (active and control) was slight and not clinically relevant, such as about 5%, the relevance of this finding lies in the over time change. In other words, the control group showed a trend to the reduction of MEF_50, whereas the children who took Lertal® exhibited an increase of MEF₅₀ within one year. This outcome could mean a potential preventive effect towards the possible asthma onset in patients with allergic rhinitis. FEF_25-75, and consistently MEF₅₀, has been reported the most sensitive marker able to detect the progression from rhinitis to asthma as reported in some studies (22-24).

These outcomes could depend on the immune-modulatory property of the 3 components of the nutraceutical as recently described (9,10).

On the other hand, this study had some limitations including the open design and the lack of the proofs concerning a real prevention of asthma onset.

In conclusion, the present study showed that a course with a multicomponent nutraceutical could prevent the MEF₅₀ decline in children with allergic rhinoconjunctivitis.

Conflict of interest:

Each author declares that he or she has no commercial associations (e.g. consultancies, stock ownership, equity interest, patent/licensing arrangement etc.) that might pose a conflict of interest in connection with the submitted article