*Article* **Effects of the Traditional Mediterranean Diet in Childhood Recurrent Acute Rhinosinusitis**

**Fernando M. Calatayud-Sáez 1,\* , Blanca Calatayud <sup>2</sup> and Ana Calatayud <sup>3</sup>**


**Abstract:** Introduction: There are more and more studies that demonstrate the anti-inflammatory effects of the traditional Mediterranean diet (TMD). The aim of the study was to assess the effects of an intervention with the TMD in patients with recurrent acute and chronic rhinosinusitis. Material and Methods: We performed a pretest–posttest comparison study in 114 patients (56 girls and 58 boys) aged one to five years who had three or more acute rhinosinusitis episodes in the period of 1 year. They were included for a year in the nutritional program "Learning to eat from the Mediterranean". The anthropometric, clinical, and therapeutic characteristics were studied. Results: All the studied indicators showed a positive and statistically significant evolution. Of the patients, 53.5% did not have any episode of acute rhinosinusitis, and 26.3% had only one, compared to the 3.37 they had on average in the previous year. The use of antibiotics decreased by 87.6%. The degree of satisfaction of the families was very high. The Mediterranean Diet Quality Index (KIDMED) that assesses the quality of the TMD rose from 7.7 to 11 points. Conclusions: The adoption of the TMD could have promising effects in the prevention and treatment of recurrent acute and chronic rhinosinusitis, limiting the pharmacological and surgical intervention in many of these patients.

**Keywords:** acute rhinosinusitis; acute recurrent rhinosinusitis; chronic rhinosinusitis; Mediterranean diet; nutritional evaluation; nutritional therapy

#### **1. Introduction**

At the beginning of the school year and with the arrival of winter, young children are prone to illness from upper respiratory tract infections (URTI), which can range between six and eight episodes a year. Most of these colds tend to resolve spontaneously within a week or two. However, 5–10% of patients develop bacterial complications, including acute rhinosinusitis (ARS) and acute otitis media (AOM). It is estimated that between 6% and 13% of children will have had an episode of ARS by three years of age [1,2]. Although it is usually a self-limited disease, it becomes one of the most frequent causes of antibiotic prescription in childhood, behind otitis and tonsillitis [3,4]. ARS is mainly characterized by the excessive prolongation of the symptoms of the common cold beyond 10 days, with difficulty in nasal breathing, mucopurulent discharge, persistent cough predominantly at night, difficulty in falling asleep, loss of appetite, and sometimes vomiting of phlegm [5]. Often there is a spontaneous improvement after conservative treatment with hypertonic saline sprays or irrigations [6]. When the general condition is more affected, or in young children, it may be necessary to use antibiotics [7]. Some patients lengthen the usual colds over and over again, causing recurrent ARS (RARS), which do not usually cause fever, and thus predisposes some parents not to come to the consultation and ends up turning into chronic rhinosinusitis (CRS). They are patients who have persistent green mucus, significant nasal obstruction, difficulty falling asleep and a persistent cough, although with

**Citation:** Calatayud-Sáez, F.M.; Calatayud, B.; Calatayud, A. Effects of the Traditional Mediterranean Diet in Childhood Recurrent Acute Rhinosinusitis. *Sinusitis* **2021**, *5*, 101–115. https://doi.org/10.3390/ sinusitis5020011

Academic Editor: Sy Duong-Quy

Received: 29 July 2021 Accepted: 26 August 2021 Published: 2 September 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

little effect on the general condition. This persistent inflammatory state contributes to the enlargement of the local lymphatic tissue, such as the palatine tonsils and the adenoids, leading to a space conflict [8]. They often present with worsening clinical attacks or other complications, such as recurrent acute otitis media (RAOM), otitis media with effusion (OME), persistent nasal obstruction (PNO) and recurrent wheezing or childhood asthma (SR) [9,10]. The diagnosis of ARS is not straightforward and can be considered as a clinical challenge, as it is generally performed on subtle clinical grounds, with the absence of specific tests. It is difficult to distinguish when a viral process has become bacterial [11]. Routine imaging is not recommended precisely because of its lack of specificity [12–14]. Pharyngeal exudates are also not useful since they do not correlate with sinus exudates. The most common bacterial species are: streptococcus pneumoniae, Hemophilus influenzae, Moraxella catarrhalis, and streptococcus pyogenes [15,16]. The treatment of RARS and CRS is controversial; several types of antibiotics have been used with limited results, since after initial improvement, patients eventually relapse [9,17]. Corticosteroid irrigations through the nasal passages and oral corticosteroids have also been used based on the few studies conducted in children with different results [1,18–20]. Mucolytics, expectorants, and antihistamines have not been shown to be helpful [21,22]. The pneumococcal vaccine does not appear to have decreased the incidence of ARS [13]. In the last case and after having failed with the pharmacological treatment, surgical intervention is usually indicated, with the oblation of the adenoids and/or the palatine tonsils, without the results being entirely satisfactory [23].

There are more and more studies that demonstrate the anti-inflammatory effects of the Mediterranean diet [24], which has allowed us to develop the hypothesis that recurrent inflammatory episodes of the respiratory mucosa are closely related to the abandonment of the traditional diet. This anti-inflammatory action is based on the reduction of pathologies related to oxidative stress, chronic inflammation, and the inflammatory system. Our hypothesis is that diet and individual nutrients can influence the resolution of RARS by stabilizing the inflammatory and immune mechanisms. We have previously conducted studies on the effects of the Mediterranean diet on URTI and their frequent bacterial complications [25], such as recurrent acute otitis media [26], otitis media with effusion [27], persistent nasal obstruction [28], and childhood asthma [29], with satisfactory results. We have also applied the Mediterranean diet in infants since birth and have observed a lower incidence of habitual inflammatory pathology [30]. Following our main line of argument in which we relate recurrent inflammatory episodes with the abandonment of the traditional diet, we have carried out this study on the effects of a traditional Mediterranean diet (TMD) in patients diagnosed with recurrent acute and chronic rhinosinusitis.

#### **2. Material and Methods**

#### *2.1. Study Design*

The design corresponded to a prospective quasi-experimental study of the comparison of before and after (pre/posttest) of a single group, with each patient examined for one year. The study consecutively included patients aged 1 to 5, diagnosed with RARS and CRS, attending a primary attention pediatrics office between May 2010 and November 2018, with the informed consent of the parents or legal guardians. This study was carried out in the Mediterranean area, in the community of Castilla la Mancha (Spain).

Patients with anatomical abnormalities, allergies, or who had been treated surgically were excluded from the study. The study consisted of comparing the incidence of RARS and CRS in the previous and subsequent years after applying the TMD. The intervention focused on food re-education based on the TMD through the use of the nutritional education program "Learning to eat from the Mediterranean", which was used in previous studies [12,13]. This program consists of a series of visits with the nutritionist and the pediatrician, who propose to assist the family. Visits are monthly for the first 4 months and bimonthly until the year is completed. The first visit evaluates the diet made by each child and his/her family, and changes in the usual diet are proposed by making schemes, culi-

nary recipes, example menus, etc. Most of the families were accustomed to the traditional (Mediterranean) diet, although its implementation was highly contaminated by industrial pressure. Thus, it was necessary to help them differentiate one from the other. A baseline anthropometric assessment is also performed. Patients were monitored over the course of a year, valuing weight, stature, growth, clinical evolution, treatment needs, adherence to the TMD, and the degree of satisfaction of the families. An explanatory diagram is shown in Figure 1. The study was approved by the Research Committee of the University General Hospital of Ciudad Real (Internal code: C-95, Act 03/2017). dustrial pressure. Thus, it was necessary to help them differentiate one from the other. A baseline anthropometric assessment is also performed. Patients were monitored over the course of a year, valuing weight, stature, growth, clinical evolution, treatment needs, adherence to the TMD, and the degree of satisfaction of the families. An explanatory diagram is shown in Figure 1. The study was approved by the Research Committee of the University General Hospital of Ciudad Real (Internal code: C-95, Act 03/2017).

pediatrician, who propose to assist the family. Visits are monthly for the first 4 months and bimonthly until the year is completed. The first visit evaluates the diet made by each child and his/her family, and changes in the usual diet are proposed by making schemes, culinary recipes, example menus, etc. Most of the families were accustomed to the traditional (Mediterranean) diet, although its implementation was highly contaminated by in-

*Sinusitis* **2021**, *5*, x 3 of 16

**Figure 1.** Study design diagram. **Figure 1.** Study design diagram.

#### *2.2. Study Variables: Clinical Evolution and Treatment Parameters*

*2.2. Study Variables: Clinical Evolution and Treatment Parameters*  The study variables were the number of ARS episodes per person and year. RARS is characterized by ARS episodes that last less than 30 days and are separated from each other by at least 10 days, during which the patient is asymptomatic. The patient must present 3 ARS episodes in a period of less than 6 months, or 4 or more in a period of less than 12 months. We also took into account patients with CRS, when episodes of rhino-The study variables were the number of ARS episodes per person and year. RARS is characterized by ARS episodes that last less than 30 days and are separated from each other by at least 10 days, during which the patient is asymptomatic. The patient must present 3 ARS episodes in a period of less than 6 months, or 4 or more in a period of less than 12 months. We also took into account patients with CRS, when episodes of rhino-sinus inflammation lasted more than 90 days, with persistent residual respiratory symptoms [4,5,31].

sinus inflammation lasted more than 90 days, with persistent residual respiratory symptoms [4,5,31]. The following variables were considered, as they are closely related to the pathology studied: upper respiratory tract infections (URTI), acute otitis media (AOM), otitis media with effusion (OME), persistent nasal obstruction (PNO), and recurrent wheezing (RW). Likewise, emergency care, symptomatic drugs, and prescribed antibiotics were assessed, all of which were assessed by person and year. A basic otorhinolaryngological examination was performed that included rhinoscopy, pharyngoscopy, otoscopy, the assessment of the presence of trans-tympanic fluid with a portable tympanometer (MicroTymp'3®, Welch Allyn, New York, NY, USA), an audiometry assessment in the collaborating children with a portable audiometer (Audioscope®, Welch Allyn, New York, NY, USA), the intentional assessment of the face (adenoid facies), a cervical lymphadenopathy, and finally a clinical assessment was made of the degree of involvement of the PNO (mild, moderate, or severe). An episode of URTI was defined by two or more of the following criteria: fever greater than 38 °C measured with a tympanic thermometer, nasal congestion or mouth breathing, runny nose, odynophagia, and cough [25]. AOM was defined following The following variables were considered, as they are closely related to the pathology studied: upper respiratory tract infections (URTI), acute otitis media (AOM), otitis media with effusion (OME), persistent nasal obstruction (PNO), and recurrent wheezing (RW). Likewise, emergency care, symptomatic drugs, and prescribed antibiotics were assessed, all of which were assessed by person and year. A basic otorhinolaryngological examination was performed that included rhinoscopy, pharyngoscopy, otoscopy, the assessment of the presence of trans-tympanic fluid with a portable tympanometer (MicroTymp'3®, Welch Allyn, New York, NY, USA), an audiometry assessment in the collaborating children with a portable audiometer (Audioscope®, Welch Allyn, New York, NY, USA), the intentional assessment of the face (adenoid facies), a cervical lymphadenopathy, and finally a clinical assessment was made of the degree of involvement of the PNO (mild, moderate, or severe). An episode of URTI was defined by two or more of the following criteria: fever greater than 38 ◦C measured with a tympanic thermometer, nasal congestion or mouth breathing, runny nose, odynophagia, and cough [25]. AOM was defined following the criteria of the American Pediatric Association Guide: (1) acute presentation; (2) presence of exudate in the middle cavity of the ear demonstrated by tympanic bulging, pathological pneumatoscopy, or otorrhea; (3) inflammatory signs and symptoms such as earache or obvious redness of the eardrum [26,32]. OME was considered when the bilateral exudate or effusion

persisted for more than 3 months, or more than 6 if it is unilateral [27]. PNO was defined as persistent difficulty in breathing adequately through the nose, with associated respiratory symptoms, such as mouth breathing, snoring, difficult breathing in sleep, respiratory arrest when sleeping (apnea), restless sleep, hyperflexion postures of the neck in order to sleep, drowsiness or a feeling of not having rested properly, adenoid facies, and swallowing difficulties [28]. RS or childhood asthma was defined as a situation in which three or more episodes of wheezing and/or coughing occur, in a clinical setting in which the diagnosis of asthma is the most likely, after excluding other less frequent processes [29]. In patients suspected of allergic processes, tests were carried out to rule them out.

#### *2.3. Clinical and Therapeutic Evaluation Rate Performed on Parents or Guardians*

To assess the clinical evolution of the patients, a questionnaire was designed, addressed to the parents or guardians, in which the symptoms related to RARS and CRS were evaluated, such as nasal breathing, nocturnal cough, difficulties falling asleep, recurrent colds and their complications, the intensity of the clinical symptoms, tolerance and difficulties with the diet carried out, and the degree of satisfaction with the therapeutic effects of the nutritional intervention. For each question in the questionnaire, one can answer the improvement observed with: 3: much, 2: quite, 1: something, 0: nothing. Ten questions referred to the clinic and treatment in the previous four weeks and a maximum of 30 (good control) to a minimum of 0 (poor control) was scored. A patient was considered to be poorly controlled when the total score was equal to or less than 20 (Table 1).


**Table 1.** Clinical and therapeutic evaluation index in rhinosinusitis. Responses from the parents or guardians regarding the improvement observed: 3: much, 2: quite, 1: something, 0: nothing.

\* is set at 4 and 12 months.

Are you satisfied with the results? 2.45 2.91

#### *2.4. Parameters of Weight Statural Evolution*

By limiting foods that are part of the new Western food culture, we have evaluated the correct weight statural development of the patients included in the study. To do this, we collected anthropometric data, such as weight, height, skinfolds, and perimeters of the arms, abdomen, and waist, and with them, we calculated the body mass index, lean mass, and body fat mass [33].

#### *2.5. Parameters of Adherence to the TMD*

To evaluate the dietary habits of patients and their families, we used the Mediterranean Diet Quality Index (KIDMED) test [34,35] and the TMD test that we presented in previous works with the intention of covering the proposed changes by the TMD [33]. The KIDMED test is one of the most prestigious for evaluating the quality of children's nutritional intake based on the TMD. It consists of a questionnaire of 16 questions that must be answered affirmatively/negatively (yes/no). Affirmative answers to the questions that represent a negative connotation in relation to the Mediterranean diet (there are four) are worth −1 point, and affirmative answers to the questions that represent a positive aspect in relation to the Mediterranean diet (there are 12) are worth +1 point. Negative

answers do not score. Therefore, this index can range from 0 (minimum adherence) to 12 (maximum adherence). In order to measure the newly proposed points, we developed a complementary test (the traditional Mediterranean diet test or the TMD test) with the same structure, to which we have added nutritional and behavioral questions that—in our opinion—are not reflected in the KIDMED test. This test consists of 20 questions that must be answered affirmatively/negatively. Unlike the KIDMED test, in the TMD test, all the questions are positive. They are therefore scored with one point for each affirmative answer, and the results can range between 0 and 20 points. A test score below or equal to 7 points is considered 'poor quality', a score between 8 and 14 points is considered as 'need to improve', and scores above 15 points are considered as 'optimal traditional Mediterranean diet'. At each visit, we evaluate the nutritional tests, and together with the patients and their parents we analyze any difficulties that may have arisen and examine how we could modify the behavior to obtain the best results. Both questionnaires allow the KIDMED index and the TMD index to be calculated. According to scores obtained in the KIDMED questionnaire, three degrees of the quality of the Mediterranean diet can be obtained: (a) 'good' or 'optimal', when the score is equal to or greater than eight; (b) 'average' or 'need to improve diet or nutritional habits', when the score is between four and seven, inclusive; and (c) 'poorly adapted' or 'low-quality diet', when the score is equal to or less than three. According to the scores obtained in the TMD index, three grades are obtained: low quality ≤7, moderate quality 8–14, optimal quality >14. Physical activity and other variables of the Mediterranean lifestyle were not considered, programmed, or monitored, but rather were included only as general recommendations.

#### *2.6. Foundations of the Traditional Mediterranean Diet*

This diet is characterized by a high content of fresh, raw, perishable, and seasonal foods, rich in vegetable fiber, minerals, vitamins, enzymes, and antioxidants; an abundance of fruits, vegetables, legumes, and whole grains, one of whose characteristics is its low to moderate glycemic index; sufficient polyunsaturated fats from crude oils, nuts, seeds, and fish; low protein and saturated fat content of animal origin; and a low use of precooked and industrial foods. This means, in daily practice, the limitation of products such as white bread, industrial pastries, cow's milk, red and processed meats, sugary industrial beverages, and precooked fast food [36]. The TMD is based on the Decalogue that the Foundation of the Mediterranean diet proposes to us through its website (Table 2) [37].

**Table 2.** The Mediterranean diet. Ten basic recommendations.



This has been proclaimed a cultural heritage and an intangible heritage of humanity by Unesco [38]. In Table 3, we expose the differences between the TMD and the diet promoted by "Western civilization".


**Table 3.** Differences between the traditional Mediterranean diet and the "Western civilization" diet.

Sample size and statistical analysis: To calculate the sample size, a significance level of 0.05 and a power of 80% was used, assuming a decrease in the degree of involvement of ARS per patient and year of 1 unit, and a standard deviation of 3.5 units, adjusting to a 25% loss, which resulted in a sample size of 80 patients. For the analysis of the results, the statistical package SPSS 15.0 was used. A descriptive analysis was carried out with statistics of central tendency and dispersion for the quantitative variables and absolute and relative frequencies for the qualitative variables. The comparison of the results of the different variables before and after the intervention was carried out by means of the Student's *t*-test for paired data when the variables followed a normal distribution, or by the Wilcoxon test when they did not adjust to normal, after checking with the Shapiro–Wilk test.

#### **3. Results**

Participation was proposed in a program called 'Learning to eat from the Mediterranean'. The families of 131 patients met the RARS and RSC inclusion criteria. Nine refused to participate. From the 122 patients included, eight left the program after the first sessions. Three were due to social or personal difficulties in implementing the diet, two were due to the disagreement with the limitations of certain foods, and three were due to surgical interventions indicated by the otorhinolaryngology service and not coordinated with our team. The study was thus completed with a total of 114 patients (56 girls and 58 boys) with an average age of 2.9 years. All of the patients included in the study were evaluated at 4 and 12 months after the initial visit. The results obtained were similar in both sexes, and are thus collated together (Table 4).

**Table 4.** Sample characteristics. The average age is 2.6 years.


\* Mean ± standard deviation; BMI: body mass index.

Table 5 shows the evolution of the patients with the number of ARS episodes in the previous year and the following year after the application of the nutritional program; ARS episodes per child and year were assessed. The evolution of other bacterial complications of the oropharynx is also exposed.


**Table 5.** Evolution during the previous year and during the year of treatment. and year 3.37 ± 1.21 0.32 ± 0.47 0.01 Number of upper respiratory tract infections (URTI) per child

**Table 5.** Evolution during the previous year and during the year of treatment.

of the oropharynx is also exposed.

Number of episodes of acute rhinosinusitis (ARS) per child

*Sinusitis* **2021**, *5*, x 7 of 16

\* Mean ± standard deviation.

We have evaluated the degree of clinical involvement of children with RARS and CRS and we have recorded the mean of their total score before and after the treatment. We have also assessed the number of times the patients visited the emergency department in the previous year and the following year, as well as the antibiotic treatment cycles they received during their inflammatory processes and symptomatic treatment, such as paracetamol, saline sprays, anti-inflammatory drugs, or expectorant mucolytics (Figure 2). We have evaluated the degree of clinical involvement of children with RARS and CRS and we have recorded the mean of their total score before and after the treatment. We have also assessed the number of times the patients visited the emergency department in the previous year and the following year, as well as the antibiotic treatment cycles they received during their inflammatory processes and symptomatic treatment, such as paracetamol, saline sprays, anti-inflammatory drugs, or expectorant mucolytics (Figure 2).

Table 5 shows the evolution of the patients with the number of ARS episodes in the previous year and the following year after the application of the nutritional program; ARS episodes per child and year were assessed. The evolution of other bacterial complications

 **Previous Year \* Year of Treatment \*** *p*

#### **Figure 2.** Evolution of the main variables of the study. **Figure 2.** Evolution of the main variables of the study.

The clinical evaluation test of the patients is shown in Table 1, which shows the assessment of the families regarding the evolution of the process and the difficulties of The clinical evaluation test of the patients is shown in Table 1, which shows the assessment of the families regarding the evolution of the process and the difficulties of treatment. The anthropometric variables before, at four months, and after intervention, are set out in Table 6. The mean weight increase the year before the study was 2.33 kg compared to the current 2.64 kg, and the increase in average height was 8.8 cm compared to 9.4 cm today.


**Table 6.** Anthropometric assessment at the start, after four months, and after one year.

\* Mean ± standard deviation.

The mean value of the KIDMED index at the beginning of the program was 7.7 ± 1.82 points; 24.6% of the patients obtained a qualification according to the KIDMED test of "need to improve" and 69.3% obtained the qualification of "optimal diet". At the end of the study, 90.4% of the children obtained optimal levels with a mean of 11 points, mean difference of 2.11 ± 0.10 (95% CI: 1.91–2.31 *p* < 0.01). According to this data, the average value of the KIDMED index evolved from a score considered medium-high at the beginning of the program to an optimal value at the end of the program (Table 7, Figures 3 and 4). treatment. The anthropometric variables before, at four months, and after intervention, are set out in Table 6. The mean weight increase the year before the study was 2.33 kg compared to the current 2.64 kg, and the increase in average height was 8.8 cm compared to 9.4 cm today. **Table 6.** Anthropometric assessment at the start, after four months, and after one year.

**4 Months of Treat-**



**Figure 3.** The KIDMED and the TMD tests evolution. **Figure 3.** The KIDMED and the TMD tests evolution.

> Optimal quality Need to improve Poor quality

69.3

**Begin**

24.6

Optimal quality Need to improve Poor quality

6.1

9.6 3.5 **4 months** 7.0 2.6 **1 year** At the beginning of the study, the mean value of the TMD test was 6.79 ± 1.98, qualifying as a poor-quality diet; 89.5% of the sample obtained a score below eight points (poor-quality diet) and 10.5% obtained a score between eight and fourteen points (need for improvement). At the end of the study, the mean score was 16.78 ± 1.90 points, qualifying as an optimal traditional Mediterranean diet. The TMD test evolved from levels considered to be low quality to optimal levels (Table 8 and Figure 5). Despite the good score obtained

90.4

Optimal quality Need to improve Poor quality

86.8

**Figure 4.** Evolution of the quality of diet, measured using the KIDMED test.

with the KIDMED test, the patients maintained the incidence of ARS. However, when applying the TMD test, we obtained statistically significant results in the evolution of ARS. **Figure 3.** The KIDMED and the TMD tests evolution. Begin 4 month 1 year Begin 4 month 1 year

0

5

10

15

6.8

*Sinusitis* **2021**, *5*, x 8 of 16

**Table 6.** Anthropometric assessment at the start, after four months, and after one year.

**At the Start of Treatment \*** 

\* Mean ± standard deviation.

10.1 11

**KIDMED test Evolution**

BMI (body mass index) 16.13 ± 1.42 15.91 ± 1.23 15.80 ± 1.38 0.02 Fat mass (%) 14.91 ± 2.72 14.72 ± 2.55 14.80 ± 2.39 0.02 Lean mass (%) 12.19 ± 2.49 13.00 ± 2.28 14.44 ± 2.18 0.03

to 9.4 cm today.

4).

0

5

10

15

7.7

treatment. The anthropometric variables before, at four months, and after intervention, are set out in Table 6. The mean weight increase the year before the study was 2.33 kg compared to the current 2.64 kg, and the increase in average height was 8.8 cm compared

**4 Months of Treat-**

The mean value of the KIDMED index at the beginning of the program was 7.7 ± 1.82 points; 24.6% of the patients obtained a qualification according to the KIDMED test of "need to improve" and 69.3% obtained the qualification of "optimal diet". At the end of the study, 90.4% of the children obtained optimal levels with a mean of 11 points, mean difference of 2.11 ± 0.10 (95% CI: 1.91–2.31 *p* < 0.01). According to this data, the average value of the KIDMED index evolved from a score considered medium-high at the beginning of the program to an optimal value at the end of the program (Table 7, Figures 3 and

**ment \* 1 Year of Treatment \*** *<sup>p</sup>*

14.5 16.81

**TMD test Evolution**

**Figure 4.** Evolution of the quality of diet, measured using the KIDMED test. **Figure 4.** Evolution of the quality of diet, measured using the KIDMED test.



cream, etc.).

*Sinusitis* **2021**, *5*, x 9 of 16

**Table 7.** The KIDMED test (%).

 **At the Start After 4** 

One piece of fruit per day 75.4 66.2 85.1 One+ piece of fruit per day 20.2 17.7 78.9 One vegetable per day 71.9 63.1 84.2 Vegetables more than once per day 10.5 9.2 63.2 Regularly eats fresh fish (2–3 times/week) 76.3 66.9 84.2 Visits fast food restaurant once or more per week 17.5 15.4 0.9

Legumes 1–2 times/week 78.9 69.3 85.1 Pasta and rice every week 78.1 68.5 84.2 Cereal or derivative for breakfast 81.6 71.6 84.2 Regularly eats dried fruit and nuts 14.9 13.1 42.1 Olive oil used at home 82.5 72.3 85.1 No breakfast 10.5 9.2 4.4 Dairy at breakfast 82.5 72.3 84.2

Factory-baked goods for breakfast 33.3 29.2 0.9 Two yoghurts or 40 g cheese/day 78.1 68.5 84.2 Sweets and snacks every day 27.2 23.9 4.4

At the beginning of the study, the mean value of the TMD test was 6.79 ± 1.98, qualifying as a poor-quality diet; 89.5% of the sample obtained a score below eight points (poorquality diet) and 10.5% obtained a score between eight and fourteen points (need for improvement). At the end of the study, the mean score was 16.78 ± 1.90 points, qualifying as an optimal traditional Mediterranean diet. The TMD test evolved from levels considered to be low quality to optimal levels (Table 8 and Figure 5). Despite the good score obtained with the KIDMED test, the patients maintained the incidence of ARS. However, when applying the TMD test, we obtained statistically significant results in the evolution of ARS.

**Months After 1 Year** 

**Figure 5.** Evolution of the quality of diet, measured using the TMD test. **Figure 5.** Evolution of the quality of diet, measured using the TMD test.

#### **Table 8.** The traditional Mediterranean diet test (%). **4. Discussion**

 **Start 4 Months Year**  Minimum two pieces of fruit every day. 28.9 76.3 92.1 Fresh vegetables at every meal, as a first course, or as part of the main course 32.5 58.8 71.9 Limited sugar intake (sweetened breakfast cereal, sweetened yoghurts or milkshakes, cakes, soft drinks, sugary biscuits, sweets, ice-12.3 72.8 80.7 Sporadic use of potatoes (1–2 times/week) and preferably not fried. 26.3 77.2 86.0 In view of these results, we suggest that the traditional Mediterranean diet could help in the prevention and also in the control of RARS and CRS, improve their treatment, and limit pharmacological and surgical intervention. At the end of the year of the intervention, less than 5% of the patients treated met the criteria to be classified as having RARS and CRS. Of the patients, 53.5% did not have any ARS, and 26.3% had only one, when the usual issue with the conventional treatment is that new episodes would have been repeated and would have ended up in the OR service. We had few episodes of CRS, probably because many of the patients already followed an acceptable Mediterranean diet, and because when they reached three to four annual episodes of ARS, we incorporated them into the TMD. RARS and CRS often overlap and it is difficult to know when a new rhinosinusitis episode starts or when it is a relapse of a process that has not yet been resolved [5]. In our study, most of the patients were diagnosed with RARS.

> The number of ARS episodes decreased by 90.5%, from a mean of 3.37 to less than 0.32% episodes per year. Although with age the effectiveness of the immune system increases and recurrent inflammatory episodes tend to disappear spontaneously, such a rapid evolution in the disappearance of symptoms could not be anticipated, which resulted in preventing the patients from having prolonged pharmacological treatments and undergoing surgery. Thus, we deduce that the nutritional intervention was beneficial for them. The degree of intensity of the ARS decreased significantly, so that not only did the total number of ARS episodes decrease, but there was also less involvement and fewer symptoms in the patients who followed the nutritional guidelines. It is important to note that during the time that the patients were enrolled in the study, we were extending the application of the TMD to the entire pediatric population (siblings, relatives, patients with other recurrent pathologies, and infants under two years of age). This led to a progressive decrease in the number of patients diagnosed with ARS, thus delaying the achievement of the sample size [30]. As we had already verified in previous studies, the URTI [25], which are one of the precipitating reasons for bacterial involvement of the paranasal sinuses, decreased significantly. In our study, there was 60% less URTI than in the previous year.

> The number of other bacterial complications decreased by 88.8% (4.31 in the previous year versus 0.72 in the year of intervention); 61% of the patients did not have any bacterial complication during the nutritional intervention period, 28% had only one in the entire year, and 10% had two, compared to the more than four episodes they had on average in the previous year. Children with PNO went from a mild-moderate intensity profile to not at all-mild [28]. Likewise, one of the most frequent reasons for attending pediatric emergencies is the discomfort caused by ARS, with worsening of the URTI and difficulties in breathing through the nose and being able to fall asleep; there was a significant reduction of 88.5% in emergencies compared to the previous year. As a consequence of the decrease in URTI, ARS, and other bacterial complications, symptomatic treatment decreased by 57%. Likewise, antibiotic treatment was reduced by 87.6%, which allows us to verify a greater benignity of the infectious processes. The degree of satisfaction shown by the parents in the clinical evaluation test was high, with scores indicating a good clinical and therapeutic

evolution. In the first four months, improvements were already observed compared to the situation of the previous year, so that loyalty increased and monitoring was easier.

There was a good tolerance to the proposed diet, with easy adaptation and without great culinary difficulties. The main difficulty was the fulfillment of the diet, as they were proposed to make a homemade, familiar diet of fresh products that must be prepared, and the parents did not always have the time and dedication to do it properly. The presence of a dietitian-nutritionist was essential to guarantee the compliance with the the TMD. By the end of the program, the dietary habits of the patients had improved in the sample as a whole; an increase in the number of patients consuming fruits, vegetables, nuts, whole grains, and fermented dairy products was observed. In general, the consumption of proteins of animal origin was reduced considerably, especially cow's milk, red meat, and meat products. The consumption of processed foods also decreased, especially industrial pastries. Prior to the development of our study, we promoted the application of a validated test, such as the KIDMED test [34], with the intention of preventing and treating inflammatory and recurrent diseases, as well as preventing becoming overweight and obese [33]. Despite this, we did not obtain satisfactory results, so we decided to implement a new TMD test, which collected information about important aspects of the Mediterranean diet that had not previously been detailed. Many of the children who had an optimal KIDMED test failed on the TMD index. It was only when they began to show improved scores with the new test that we obtained satisfactory results. In the KIDMED test, some variables that we believe are important are not considered. For example, no differences are noted between refined cereals and whole grains, nor are there any references to the consumption of sugar or sugary industrial juices. Additionally, in general, glycemic index/glycemic load is not taken into account. In the lipid section, saturated fat consumption is neither limited nor evaluated. The test does not allow for the detection of an excess consumption of animal proteins. Additionally, no assessment is made of the consumption of raw food, nor is the minimum amount to be taken specified. Serving sizes and schedules are not taken into account. Completing the KIDMED test has not been shown to be effective in our study. We believe that these small nuances that we have proposed in the TMD test are important for obtaining satisfactory results in the examination of recurrent inflammatory diseases, in particular RARS. The patients showed satisfactory predicted growth rates. Their weight, height, and BMI percentile evolved as expected. A positive result was the slight decrease in the BMI and fat mass levels and a small increase in height and lean body mass.

Although these data suggest that the intake of healthy foods and/or the avoidance of non-traditional foods may play an important role in the control of ARS, there are almost no bibliographic references in the scientific literature. We want to highlight that most of the studies published on the treatment of RARS and CRS are based on the application of actions external to the body, such as the use of drugs or surgical intervention. The nutritional factors have not been taken into account, when the deconfiguration of the inflammatory system and the immune system due to inadequate food is likely at the base of these pathologies. The etiology and pathogenesis of this inflammation are often unclear, although this is believed to represent an inappropriate or excessive immune response to an external stimulus inhaled through the nasal airways [1].

The research has suggested the protective effect of breastfeeding for at least 6 months, although other risk factors accumulate after that age [39]. Among them, the early introduction of adapted milk has been noted [40] as well as the abuse of antibiotics [41]. A pan-European study has shown that children consuming excessive refined flours and processed animal-based products and having a diet poor in fruit and vegetables have high inflammatory markers, and as a whole, they can be considered to be in a pro-inflammatory state [42]. Likewise, ARS patients have been shown to have an altered regulation of key immune mediators during good health and pathogenesis and are amenable to treatment by immunomodulatory intervention [43]. Predominantly eating foods with a low glycemic index/load typical of the TMD—helps to control insulin levels; this hormone may interfere in the formation of anti-inflammatory eicosanoids, by blocking the ∆-desaturase enzyme [44].

Similarly, the TMD is rich in vitamins, minerals, and antioxidants, many of which are indispensable co-factors in the enzymatic chemical reactions involved in the body's immune processes. Children with recurrent inflammatory infections have been shown to have poor responses to pro-inflammatory cytokines and antiviral chemokines [45,46]. High-mobility group box protein 1 (HMGB1), that acts as a mediator between innate and acquired immunity, is overexpressed and can play a role in the progression of CRS and RARS, acting as an inflammatory marker and cytokine [47].

There is a growing interest in understanding the alterations of the naso-sinus microbiome as a causative factor of the disease. Likewise, it has been considered that there is a dysfunctional naso-sinus mucosa, in which defects of the epithelial surface may be the basis of the etiology and pathogenesis of the disorder [48–51]. It has been shown that an inadequate diet, away from the traditional diet, can alter the rhino-sinus microbiota and cause intestinal dysbiosis [52]. Biofilms provide a protected environment for pathogens and can be responsible for persistent or recurrent diseases [1]. The immune system may not recognize foreign, infrequent, or foreign microbial germs, and cause the cytokines or other cell signaling molecules to react, which alter inflammatory mechanisms and leave the respiratory mucosa in a permanent pro-inflammatory state. In this way, in the face of small stimuli, such as simple catarrhal viruses, hyper-reactivity of the mucous membranes would be triggered, with flowery symptoms, which would end up causing the usual complications and in particular the RARS. Adenoid hypertrophy and adenoiditis contribute significantly to the pathogenesis of RARS, being one of the main differences between the involvement of children and adults [1,53]. The mechanisms by which the intestinal flora modulates the immune response are not clear, but it seems prudent to favor an intestinal microbiota typical of the human species, since evolution and genetic coding have had to configure a specific symbiosis between nutrition, the intestinal microbiota, and immunity that we should not modify.

The growing interest in the Mediterranean diet is based on its role in inflammatory diseases [54]. Several clinical and epidemiological studies, as well as experimental studies, show that the consumption of the TMD reduces the incidence of certain pathologies related to oxidative stress, chronic inflammation, and the immune system, such as cancer, atherosclerosis, or cardiovascular disease [55]. There is evidence that diet and individual nutrients can influence the systemic markers of immune function and inflammation [56]. The pro-inflammatory actions of platelet-activating factor (PAF), one of the most potent endogenous mediators of inflammation, can be favorably modulated by the TMD and regulate its metabolism [57]. The TMD is an ancient diet, dating back to way before documented history, and which has stood the test of time. Many of the foodstuffs eaten as part of the Western diet contain materials not recognized or assimilated by the human body. Many of these products are not absorbed by the intestine, thus encouraging non-specific microflora that is alien to the human intestinal microbiota. The excess "antigenic load" inherent in the Western diet of today—which has multiplied the available foodstuffs by the thousand—may misadjust our immune system, making it weaker and notably hyperplasic.

It has recently been proven that better adherence to the Mediterranean diet may be associated with a lower risk of COVID-19 [58,59], demonstrating its effect against virus infections. Secretory IgA antibodies are an important part of the immune defense against viral diseases. People who ingest Okinawan vegetables have high IgA levels and might be more likely to develop immunity against influenza RNA viruses [60].

One of the characteristics that every research study should have is that it is easily reproducible, using small groups, and with little economic cost. The work presented here is easy to reproduce in any primary care pediatric consultation, but it is not easy to perform due to the lack of nutritionists and the lack of effective monitoring of the diet.

We could not perform a study with a control group since most of our pediatric space was adhering to the Mediterranean diet and it did not seem ethical to promote a pro-inflammatory Western-type diet in a control group. Our hypothesis is precisely that the standard diet proposed by "Western civilization" is the origin of alterations

in the inflammatory and immune mechanisms, and therefore the precipitating factor of most of the inflammatory and recurrent diseases of childhood. It would have been very interesting to perform analyses that measured the response of the immune system, inflammatory markers, and the data on the modification of the microbiota when making the nutritional change.

Most of our patients have been consecutively included in the program "Learning to eat from the Mediterranean" and we have verified how the prevalence of ARS and other inflammatory recurrent diseases has decreased considerably. The change of the "model of medicine" that these research studies entail should not go unnoticed. It is no longer about remedying a disease with external drugs or surgical interventions, but the therapeutic proposal is based on providing the body with everything it needs to solve their needs and eliminate that for which it is not ready.

We can conclude by saying that the application of the traditional Mediterranean diet could have promising effects in the prevention and treatment of acute recurrent and chronic rhinosinusitis, with a notable decrease in associated inflammatory diseases, limiting pharmacological and surgical intervention in many of these patients.

**Author Contributions:** Conceptualization, F.M.C.-S.; and B.C.; methodology, F.M.C.-S.; software, B.C.; validation, F.M.C.-S.; B.C., and A.C.; formal analysis, B.C.; investigation, F.M.C.-S.; B.C., and A.C.; re-sources, F.M.C.-S.; data curation, B.C.; writing—original draft preparation, F.M.C.-S.; writing—review and editing, F.M.C.-S.; visualization, F.M.C.-S. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board (or Ethics Committee) of Hospital General Universitario de Ciudad Real (Internal code: C-95, Act 03/2017).

**Informed Consent Statement:** Informed consent was obtained from all subjects involved in the study.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


**Kremena Naydenova <sup>1</sup> , Vasil Dimitrov <sup>1</sup> and Tsvetelina Velikova 2,\***


**Abstract:** Inflammation of the upper respiratory tract in patients with allergic rhinitis (AR) may contribute to lower respiratory airways' inflammation. T-helper 17 (Th17) cells and related cytokines are also involved in the immunological mechanism of AR along with the classical Th2 cells. It is hypothesized that upon Th2 pressure, the inflammatory response in the lungs may lead to Th17 induced neutrophilic inflammation. However, the findings for interleukin-17 (IL-17) are bidirectional. Furthermore, the role of Th17 cells and their counterpart—T regulatory cells—remains unclear in AR patients. It was also shown that a regulator of inflammation might be the individual circulating specific non-coding microRNAs (miRNAs), which were distinctively expressed in AR and bronchial asthma (BA) patients. However, although several circulating miRNAs have been related to upper and lower respiratory tract diseases, their function and clinical value are far from being clarified. Still, they can serve as noninvasive biomarkers for diagnosing, characterizing, and providing therapeutic targets for anti-inflammatory treatment along with the confirmed contributors to the pathogenesis—Th17 cells and related cytokines. The narrow pathogenetic relationship between the nose and the bronchi, e.g., upper and lower respiratory tracts, confirms the concept of unified airway diseases. Thus, there is no doubt that AR and BA should be diagnosed, managed, and treated in an integrated manner.

**Keywords:** allergic rhinitis; bronchial asthma; allergy; Th17 cells; IL-17; IL-33; microRNA; miR; airway mucosal inflammation; united airway disease

#### **1. Introduction**

The evidence gathered suggests a link between the upper and lower airways, grouped as "united airway, one disease" [1–5]. The topic is critical, and the interest and involvement of the specialists are continuously increasing.

Several mechanisms explain this connection. It is well known that the nose and sinuses have a significant protective function for the respiratory tract by warming, humidifying, and purifying the inhaled air. Any condition or disease affecting the upper respiratory tract's mucosal layer impedes this protection. This leads to exposing the lower respiratory tract to the harmful effects of polluted air, irritants, and allergens [6]. Therefore, patients suffering from allergic rhinitis (AR), sinusitis, and/or nasal polyposis may exhibit airway inflammation along with bronchial hyper-reactivity. Nasal and sinus involvement is closely related to bronchial asthma at both pathophysiological and clinical levels [1,2].

This review aims to reveal the recent advances in the "united airway disease pathway," focusing on allergic rhinitis, rhinosinusitis, and other airway conditions, such as bronchial hyper-reactivity and allergic asthma. Along with the common pathophysiology, the upper and lower airway diseases share common diagnostic and treatment approaches. This is especially valid when multiple conditions present simultaneously.

**Citation:** Naydenova, K.; Dimitrov, V.; Velikova, T. Immunological and microRNA Features of Allergic Rhinitis in the Context of United Airway Disease. *Sinusitis* **2021**, *5*, 45–52. https://doi.org/10.3390/ sinusitis5010005

Received: 10 December 2020 Accepted: 15 February 2021 Published: 19 February 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

#### **2. Allergic Rhinitis in the Continuum of Airway Inflammation**

One of the most common allergic diseases is AR, affecting up to 40% of the population [7]. The prevalence in the Bulgarian population is 18.2%, as shown in a 2000 study [8]. The disease is IgE-mediated and non-infectious, affecting the nasal mucosa. The condition may involve the conjunctiva in 70–75% of cases after contact with environmental allergens [9]. Although AR is not a life-threatening disease, it significantly impairs patients' quality of life and the efficiency of daily activities [10].

Approximately 40% of patients have comorbidities such as bronchial asthma (BA), while most patients with BA (85–90%) also have concomitant AR [11]. In patients with BA, the inflammation affecting the nose and sinuses shares common pathological features with that of the lungs [1,10].

It is worth mentioning that in nasal polyposis, the inflammation is predominantly eosinophilic with local production of IgE antibodies [12]. Furthermore, nasal polyps formed by the mucosa's growth in the paranasal sinuses and that prolapse into the nasal cavity contribute to the nasal obstruction. In clinical practice, the simultaneous presence of BA, polyposis, and aspirin sensitivity is referred to as Samter's triad, or aspirin-exacerbated respiratory disease [13]. This is another proof of the united airway pathway concept.

#### **3. Upper Airway Cough Syndrome**

The relationship between the upper and lower respiratory tracts can be represented with the common symptom of coughing. The latter remains a diagnostic and treatment challenge in clinical practice. Upper respiratory tract infections play a significant role as a risk factor in the development of asthma. Moreover, they are the most common identified cause of chronic cough in adults [14]. Inflammation is common among chronic diseases characterized by coughing. Usually, the inflammatory process is spread from the upper to the lower respiratory tract [15].

In line with this, chronic inflammation that affects the upper and lower respiratory tracts is referred to as sinobronchial syndrome [16]. This syndrome includes chronic rhinosinusitis together with nonspecific inflammation of the lower airways (e.g., chronic bronchitis, bronchiectasis, and diffuse panbronchiolitis). It has been hypothesized that sinusitis occurs first, then the inflammation progresses to bronchial disease. Clinically, markers of bronchial irritation usually correlate with sinusitis severity. This hypothesis assumes that postnasal drip entering the trachea plays an essential role in developing the disease [17,18]. The anatomical relation between the upper and lower airways suggests the possible involvement of nasal discharge to provoke bronchial hyper-reactivity in patients with AR or rhinosinusitis [19]. As postnasal drip is not a diagnosis but a symptom, a broad differential diagnosis should be made, including AR, vasomotor rhinitis, viral or bacterial infections, and nasal polyps [20].

Upper airway cough syndrome (UACS) is the cause of chronic cough in 18.6–67% of cases in China [21]. Cough in patients with UACS is usually secondary due to upper airway diseases (i.e., affecting the nose and sinuses). Pekova et al. reported increased cough sensitivity in patients with AR without cough relative to healthy controls' sensitivity to cough. The difference between the two groups was predominantly pronounced during the pollen season. Nevertheless, the cough hypersensitivity syndrome observed in allergic patients may be one of the mechanisms leading to cough in patients with UACS [22].

Cough hypersensitivity to capsaicin in patients with allergic asthma increases during the birch pollen season. Increased sensitivity was observed with prolonged pollen exposure in the same patients. This observation suggests that allergic inflammation of the lower and/or the upper respiratory tract stimulates neurogenic mechanisms of significant clinical importance [23]. Explanations include that patients with AR may have an increased number of neurons that release large amounts of neuroinflammatory mediators in the nasal mucosa. Inflammatory mediators not only activate sensory neurons but also sensitize them, lowering their activation threshold.

Kaiser et al. [24] studied neuropeptides' levels in nasal secretions in patients with and without chronic cough. They found that patients with cough and postnasal drip had significantly higher levels of neuropeptides, such as calcitonin gene-related peptide (CGRP) and substance P (SP), compared to patients without complaints. This study supports and confirms the role of neuropeptides in increased nasopharyngeal discharge and cough hypersensitivity in the context of the united airway disease.

#### **4. Immune Cells Involved in United Airway Inflammation**

It was previously established that to maintain immune homeostasis, it is vital to obtain a balance between the regulatory and effectors immune cells, such as T-helper type 1 (Th1) and type 2 (Th2) cells. As the Th1/Th2 balance dysregulates, the released cytokines contribute to the development of chronic inflammation of the mucosa, resulting in autoimmune or allergic diseases [25].

It is assumed that AR is related to the first type of allergic sensitization in Coombs' classification, where the involvement of IgE antibodies is crucial [26]. Early and late phases of an allergic response are observed.

Briefly, the immunological mechanism can be represented as follows: upon contact with the mucosa, the allergen is taken up by the antigen-presenting cells, which process it and present it to Th2 cells. Activated Th2 lymphocytes release IL-4, IL-6, IL-13, etc., which interact with B lymphocytes. This interaction leads to the activation of B cells and the synthesis of specific IgE antibodies. IgE antibodies bind to their high-affinity receptors on mast cells' surfaces and, upon contact with the specific allergen, lead to cell degranulation. As a result, several mediators are released, such as histamine, leukotrienes, and prostaglandins. This description represents the early phase of an allergic response observed within the first few minutes after the allergen contact that lasts 2–3 h.

In the late phase, which occurs 4–6 h after antigenic stimulation, cellular infiltration of the mucosa consists mainly of T lymphocytes, eosinophils, and basophils. In the described Th2 response, IgE antibody production requires two main signals to switch B cells to an IgE antibody-producing plasma cell. The first signal is provided by the cytokines IL-4 or IL-13, which interact with B cell receptors. They transmit the signal by activating the tyrosine kinases of the Janus family— Janus kinase 1 (JAK1) and JAK3—which leads to phosphorylation of the STAT6 transcription regulator. The second signal for IgE switching is additional stimulation by contact between the CD40 ligand on the T cell surface and CD40 on the B cell surface [27]. It is worth mentioning that the allergen stimulation of the immune system leads to priming of the entire mucosa of the airways.

Nasal polyps are also rich in inflammatory immune cells, such as eosinophils, Th lymphocytes, plasma cells, and mast cells. Histologically, nasal polyps are characterized by an edematous stroma, eosinophilia, a thickened basement membrane, and a damaged ciliary epithelium. It is not surprising that chronic inflammation in the nasal polyps, allergic or not, resembles the bronchial mucosa inflammation observed in asthma. This once again confirms the united disease pathways of the airways. Nevertheless, in 30–70% of patients with nasal polyposis, accompanying BA is diagnosed [28].

Interestingly, it was shown that AR without polyposis or eosinophilic inflammation may not possess the common airway pathways with asthma, unlike the case where all present together [29]. Taken together, data on the united airway pathway suggest that AR should be seen as predictive risk factor for asthma [30].

#### **5. Th17 Cells Role in the Common Inflammation of the Airways**

In recent decades, discovering Th17 cells and regulatory T (Treg) cells has dramatically complicated the established Th1/Th2 paradigm. Involvement of the two counterparts— Th17 cells and Tregs—complicates the understanding of AR's pathogenesis [31]. The role of Th17 cells in neutrophil infiltration and chronic inflammation in AR and asthma is well established. Moreover, it was confirmed that the balance between Th17/Treg cells matters clinically in allergic and autoimmune diseases.

Speaking of the united airway pathway, the participation of Th17 in the pathogenesis and progression of AR and other diseases is also proven. Moreover, a correlation of IL-17 levels in the inflamed airway mucosa with the severity of the allergic disease was found [32]. asthma is well established. Moreover, it was confirmed that the balance between Th17/Treg cells matters clinically in allergic and autoimmune diseases. Speaking of the united airway pathway, the participation of Th17 in the pathogenesis and progression of AR and other diseases is also proven. Moreover, a correlation of IL-17 levels in the inflamed airway mucosa with the severity of the allergic disease was found

Many studies have proven the involvement of Th17 cells and IL-17 in the immunological mechanism of AR. A recent study by Huang et al. [33] examined Th17/Treg cells immunity in AR patients. The results showed that Th17 cells were significantly increased in the peripheral blood of patients with AR, whereas the Treg cell number was decreased. The results suggested that the Th17/Treg imbalance plays a crucial role in AR's pathogenesis and severity. [32]. Many studies have proven the involvement of Th17 cells and IL-17 in the immunological mechanism of AR. A recent study by Huang et al. [33] examined Th17/Treg cells immunity in AR patients. The results showed that Th17 cells were significantly increased in the peripheral blood of patients with AR, whereas the Treg cell number was decreased. The results suggested that the Th17/Treg imbalance plays a crucial role in AR's pathogen-

Moreover, Milovanovic et al. demonstrated that IL-17 could induce B cell switching to IgE antibody production, endorsing, once again, the involvement of Th17 in allergic diseases [34]. However, Th17 cells produce a large number of mediators, but IL-17A can directly induce IgE production. esis and severity. Moreover, Milovanovic et al. demonstrated that IL-17 could induce B cell switching to IgE antibody production, endorsing, once again, the involvement of Th17 in allergic diseases [34]. However, Th17 cells produce a large number of mediators, but IL-17A can directly induce IgE production.

A schematic picture of the immune mediators and cells involved in the airway mucosa inflammation is presented in Figure 1. A schematic picture of the immune mediators and cells involved in the airway mucosa inflammation is presented in Figure 1.

**Figure 1.** Immunological interactions in the inflamed mucosa in the concept of united airway disease. Naïve T cells differentiate either into Th2, Tregs, or Th17 cells. By secreting a distinct array of cytokines, Th17, Th2, and Treg cells connect innate and adaptive immune responses in the airway mucosa, especially during mucosal inflammation. Balance of Th17/Tegs is needed to maintain the immune homeostasis in the mucosa and to resolve the inflammation. Note: allergens are presented as different shaped objects in the airway lumen. **Figure 1.** Immunological interactions in the inflamed mucosa in the concept of united airway disease. Naïve T cells differentiate either into Th2, Tregs, or Th17 cells. By secreting a distinct array of cytokines, Th17, Th2, and Treg cells connect innate and adaptive immune responses in the airway mucosa, especially during mucosal inflammation. Balance of Th17/Tegs is needed to maintain the immune homeostasis in the mucosa and to resolve the inflammation. Note: allergens are presented as different shaped objects in the airway lumen.

Another cytokine with a role in the common airway inflammation and allergic diseases is IL-33. It is a member of the IL-1 cytokine family released in response to epithelial cell damage. IL-33 exerts many actions by interacting with the suppressor of tumorigenicity 2 (ST2) receptor. Furthermore, it can induce Th2 cytokine-mediated allergic inflammation [35]. The IL-33/ST2-induced Th2 response has been found to interact with the Th17 immune response in AR pathology [36,37]. IL-33 also induces the production of proinflammatory cytokines and participates in the pathogenesis of diseases other than AR, such as atopic dermatitis, BA, and pollinosis.

The crucial role of IL-33 in the united airway inflammation is based on bridging the innate and acquired immune responses in allergic diseases [38]. Clinically, this connection was evaluated by the reported correlation of IL-33 levels and the AR severity [39].

Other cytokines, such as those with anti-inflammatory properties—IL-10, TGF-β, and IL-35—and related to Th17 and Th22 cells—IL-22 and IL-27—might shape the allergic responses as well. Still, there are few reports on their role [40]. The cytokines related to Th17 and Treg activation while suppressing Th1 cells—IL-17, IL-22, and TGF-*β*—were found enhanced in AR patients. On the contrary, IL-35, which was shown to inhibit both Th2- and Th17-mediated allergic airway inflammation, was detected low in patients with AR, showing the possible role in the pathogenesis of allergic diseases [40].

#### **6. Diagnostic and Therapeutic Approaches in the Light of the United Airway Pathway**

By enhancing the understanding of the inflammation of the upper respiratory tract and the pathogenesis of AR and other allergic diseases, new diagnostic and therapeutic approaches can be established. They can facilitate the management and follow-up of the patients and improve their quality of life.

#### *6.1. microRNAs as a Promising Tool in United Airway Disease Diagnosis*

Promising and advanced tools for diagnosing and managing patients with AR and BA are the small non-coding RNAs, known as microRNAs (miRNA or miR). As specific gene expression regulators, miRNAs regulate many biological processes, including cell differentiation, proliferation, and survival [41]. Furthermore, they can serve as noninvasive biomarkers for diagnosis, molecular classification, severity, and relapse prediction [38]. miRNAs tend to participate in the pathogenesis of both AR and BA. It was shown that individual circulating miRNAs were distinctively expressed in AR and BA patients [42].

Moreover, few studies examined their role in clinical settings. Suojalehto et al. found increased levels of miR-143, miR-187, miR-498, miR-874, and miR-886-3p and decreased levels of let-7e, miR-18a, miR-126, miR-155, and miR-224 in BA compared to controls [42]. However, these results were independent of concomitant AR. Thus, no distinction was made between BA and AR based on these expressions.

In the second study, Suojalehto et al. [43] found upregulated expression of miR-155, miR-205, and miR-498 but downregulated expression of let-7e in the nasal mucosa of AR patients and current symptoms in comparison with AR without asthma. However, the cytokine levels (IL-4, IL-5, and IL-13) and miRNA expression profile were comparable in AR with or without AB, suggesting that concomitant asthma might have a minor impact.

In addition, an alternative to the nonsteroidal anti-inflammatory treatment, adjusting and regulating the miRNA network, may be a promising therapy approach.

#### *6.2. Biological Therapy in the Focus of United Airway Disease*

The success of all available treatment strategies for united airway disease relies on the combined targeting of all clinically presented diseases. The similar pathological pathways and common mucosal inflammation, along with the parallel incidence of AR and BA, lead to the approach for similar treatment, including biological therapy, as we showed previously [44–47].

The strategy of using biological agents has been investigated in patients with AR, BA, and other allergic diseases. Biological therapy was considered a beneficial treatment option in patients with severe uncontrolled phenotypes of diseases. Omalizumab, which represents a humanized anti-IgE monoclonal antibody, has been studied extensively for AR and BA. It confirmed its effectiveness in preventing IgE to attach to its high-affinity receptors. Moreover, omalizumab's clinical outcomes have been linked to reducing nasal

and asthma symptoms, decreasing the number of exacerbations by affecting both the upper and lower airways [47]. All of these led to an overall improvement in the quality of life of the patients.

Another monoclonal antibody used for both AR and BA—mepolizumab—acts by blocking the binding of IL-5 to eosinophils. Mepolizumab has also shown efficacy in improving the severity of eosinophilic airway diseases, especially in BA and nasal polyps [48,49].

Nevertheless, we must always have in mind that monoclonal therapy is not without systemic effects. In line with this, in patients with united airway disease due to the effects of therapy on AR improvement, it is hardly possible to design a study to distinguish the improvement in BA alone. In line with this, management of AR and BA must be carried out together to obtain better control of both diseases [50].

#### **7. Conclusions**

The concept of unified airway diseases has been the subject of attention in recent years. The pathogenetic relationship of the nose and the bronchi and alveoli, along with the observed common inflammation, provides a niche to create new diagnostic and therapeutic options.

With Th17 cells and other immune cells and mediators, gene alteration and regulation by miRNA complicate the picture of the united airway inflammation. More research here is needed to better understand the associations between the upper and lower airways. However, there is no doubt that AR and BA should be diagnosed, managed, and treated in an integrated manner.

**Author Contributions:** Conceptualization, K.N. and T.V.; writing—original draft preparation, K.N.; writing—review and editing, T.V.; visualization, T.V.; supervision, V.D. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

