Coronavirus disease 2019 is a systemic condition with a wide range of symptoms related to airways (e.g., cough, dyspnea, and sputum production) and other systems (diarrhea, abnormal heart rhythm, and headache) [1]. As of August 8, 2022, more than 581 million positive cases have been reported in the world, whereas the number of related deaths is over 6.4 million [2]. In Georgia, approximately 1,7 million people have been diagnosed with COVID-19, and 16,869 have died from the disorder. Meanwhile, approximately 12 billion vaccine doses have been administered worldwide. Long-lasting symptoms suffered 12.8-27.8% of patients recovering from SARS-CoV-2. It was shown that the prevalence of post-COVID-19 conditions 28 days to 12 months after COVID-19 infection was 54% in hospitalized individuals and 34% in non-hospitalized individuals [3]. A growing body of literature has shown that symptoms persist for at least several months in a substantial proportion of people affected by SARSCoV-2 [3, 4]. Shortness of breath, fatigue, joint pain [5], insomnia and ageusia [5], vasomotor rhinitis, and injuries in the olfactory neuroepithelium [6] are the most commonly reported symptoms; they are, therefore, associated with the post-COVID syndrome (PCS). Given the high prevalence of the history of COVID-19 in the general population, it is crucial to understand better the long-term effects of this disease on health. As practice has shown, rhinitis is common after the transfer of SARS-CoV-2 [7], although studies in this direction cannot be found in the literature [8]. Rhinitis is defined as inflammation of the nasal mucosa, which occurs annually in more than 200 million individuals worldwide [9, 10], placing a heavy burden on society and requiring huge costs for medical treatment.

As practice has shown, rhinitis is common after the transfer of SARS-CoV-2 [7]. Rhinitis is defined as inflammation of the nasal mucosa, which occurs annually in more than 200 million individuals worldwide [8, 9], placing a heavy burden on society and requiring huge costs for medical treatment. Non-allergic perennial rhinitis, i.e. VMR is a chronic form of non-infectious rhinitis, clinical signs can last more than 9 months a year and are characterized by signs and symptoms identical to those of allergic rhinitis (rhinorrhea, nasal congestion, sneezing, and post-nasal discharge) [8-10]. Unlike allergic rhinitis, the etiology of "Non allergic rhinopathy" (Vasomotor Rhinitis (VMR)) is unknown and is not related to IgE-mediated mechanisms, infections, structural lesions, systemic diseases, drug use, or eosinophilia. VMR was defined as "a chronic nasal condition with symptoms that may be perennial, persistent, intermittent or seasonal and/or elicited by recognized triggers" [11]. The manifestation of symptoms of VMR can be challenged by a variety of non-specific causes, such as changes in temperature and/or humidity, strong odors, respiratory irritants, spicy foods, and alcoholic beverages. In addition, the symptoms of VMR are characterized by the release of pro-inflammatory mediators (cytokines, leukotrienes) and cell adhesion molecules (ICAM-1), which play an important role in the processes of maturation, migration, and activation of inflammatory cells (eosinophils and mast cells). There is a correlation between inflammation, the degree of hyperactivity of the nasal cavity, and the severity of symptoms of VMR. Literature data indicate the impossibility of identifying patients with VMR by classical inflammatory markers [10] there are no special diagnostic tests for vasomotor rhinitis. The diagnosis is usually based on excluding a causal relationship with allergic irritants [12].

Despite many strategies for the treatment of VMR, to this day there is no single treatment regimen; mainly intranasal corticosteroids and antihistamines are used. The first one is effective in various forms of eosinophilia and, as a rule, is ineffective in treating symptoms [13]. Our study aimed to determine some aspects of the pathogenesis of VMR in patients with a history of COVID-19 infection and to evaluate the therapeutic efficacy of a local antihistamine drug.

The study was conducted at the First University Clinics of Tbilisi State Medical University and the National Centre of Otorhinolaryngology (Tbilisi, Georgia). Criteria for inclusion of patients in the study: shortness of breath through the nose, runny nose, itching in the nasal cavity for 6 weeks or more. Exclusion criteria from the study: patients sensitized to seasonal allergens, with a history of bronchial asthma and/or bronchial hypersensitivity, chronic rhinosinusitis, nasal polyposis or sensitivity to aspirin, pregnant women, patients in the acute phase of COVID-19 infection, nicotine users, excessive alcohol users and patients who took anti-inflammatory drugs (nasal steroids or antihistamines within the last 6 weeks). Inclusion and exclusion of patients in the study were performed according to anamnesis data.

For the correct diagnosis and differentiation among types of rhinitis, a thorough analysis of comprehensive history (anamnesis) is usually used (symptoms (i.e., duration, exposures, magnitude of reaction, patterns, and chronicity) triggers, seasonal variation, environmental influences; allergies, medical history (i.e., trauma, family, and treatment histories). The patients with allergic rhinitis were excluded based on the allergen-specific IgE test, percutaneous skin test [13, 14], and trigger identification [14]. Vasomotor rhinitis is diagnosed through exclusion; patients should have normal serum IgE levels, negative skin testing or RAST, and no inflammation on nasal cytology. The other types of rhinitis were excluded according to anamnesis data (acute viral rhinitis and rhinosinusitis, hormonal (caused by pregnancy, oral contraceptive use, and hypothyroidism), drug-induced rhinitis (angiotensin-converting enzyme inhibitors, reserpine, guanethidine, phentolamine, topical nasal decongestants, aspirin, no steroidal anti-inflammatory drugs, etc.), rhinitis medicaments (Repetitive use of topical alpha-adrenergic decongestant sprays) [14]. The term vasomotor implies an increased blood supply to the nasal mucosa, although this suggestion has not been proven. Symptoms mainly consist of congestion; hyper secretion; and, less commonly, pruritus and sneezing.

The diagnosis of non-allergic VMR was made based on subjective (frequency of sneezing, degree of difficulty in nasal breathing, nature, consistency, color of nasal discharge, as well as the color of swelling of the nasal mucosa, and turbinate, impaired olfactory function, general condition of the patient) and objective (anterior and posterior rhinoscopy, endoscopy (exclude patients with signs of purulent rhinitis or polyposis from the study); rhinomanometry (to assess difficulty in breathing and to exclude patients with concomitant diseases (curvature, polyposis, nasal valve insufficiency, the degree of nasal congestion)) studies [14]. The study design was approved by the Ethics Committee of the National Center of Otorhinolaryngology. After informed consent, patients were asked to complete the Nasal Obstruction Symptom Evaluation (NOSE) questionnaire (a simple five-question, validated survey that uses a 20-point scale to capture breathing symptoms, with higher scores indicating more severe symptoms than lower scores to assess the severity of nasal obstruction) [15]. All patients were antigen-tested or had a negative PCR test for COVID-19.

The study involved 140 volunteer market vendors (Tbilisi, Georgia) aged 28 to 58 years, of which 60 (42.9%) were women, and 80 (57.1%) were men. Patients were divided into 3 groups: Group I - patients with VMR presenting more than 6 months after infection with SARS-CoV-2 (post-COVID-19 complication) (n=58 (30 women, 28 men), 41.5%); Group II - patients with VMR without COVID-19 (n=52 (32 women, 20 men), 37.1%); in the group III were included healthy volunteers (n=30 (18 women, 12 men), 21,4%) who more than 6 months didn’t contract COVID-19. The Group who had contracted COVID-19 had expressed symptoms of the infection such as high temperature, cough, runny nose, and sore throat (mild severity of COVID-19); patients in this group were not hospitalized. In all groups 28-35-year-old patients had no comorbidity and specific medication prescriptions. As for 35-40-year-old patients’ hyperthyroidism, autoimmune hypothyroidism and prediabetes were marked. In the same age range third group patients had no demonstrated comorbidities. In the 40-58 -year-old patients of all groups (I, II, III) diabetes mellitus, high blood pressure, autoimmune hypothyroidism, arthritis, and arthrosis were presented (Table 1).

Table 1: Demographical characteristics of the studied patients (age, gender) and comorbidities.

Persons of groups I and II underwent the instrumental examination, the cytological (eosinophils, neutrophils, and leukocytes count) and biochemical investigations of nasal smear (the content of nitric oxide (NO)) and blood serum total antioxidant activity. All studies were performed on patients before and after treatment; on 3-d and 5-th days after the beginning of treatment, the patient was scheduled to consult an otolaryngologist to assess the general condition and/or identify possible side effects. Patients of groups I and II were treated for VMR with intranasal antihistamine spray- 2 sprays 2 times a day for 10 days. The healthy volunteers of group III were treated with physiological solute 2 sprays 2 times a day for 10 days. The drug's mechanism of action is based on olopatadine's ability to cause inhibition of the release of biologically active substances - inflammatory mediators (bradykinin, serotonin, histamine, leukotrienes). The effectiveness of treatment was assessed according to the subjective complaints of patients and according to objective indicators of instrumental examination. For the assessment of the effectiveness of treatment, we used a simple 3-point system introduced and successfully tested by local clinical practice in the National Centre of Otorhinolaryngology (0 score - asymptomatic patient, 1 score - minor complaints, 2 scores - moderate complaints, 3 scores - strong, pronounced complaints (sneezing was assessed by intensity and duration)).

Nasal Smears Cytological Examination

All participants collected nasal smears by scraping the mucous membrane of the medial surface of both inferior turbinates with a sterile cotton swab soaked in saline. The secretions were then spread thinly onto two glass slides (one for each side) and air-dried. The slides were numbered and sent to the pathologist for examination. The smears were stained with the May-Grunwald-Giemsa stain and the eosinophil, neutrophil, and leucocyte count was recorded in terms of the number of eosinophils per high power field (HPF).

As the cells were unevenly distributed in smears, the eosinophils, neutrophils, and leucocytes were counted in at least 50 HPFs, and the average count was recorded. This was done for smears from both the left and right nostrils; finally, an average of the two counts was calculated. To prevent subjective judgment by the investigator examining the smears, all the smears from patients and controls were coded before they were sent to the pathologist. The same observer examined all the smears.

Measurement of Nitric Oxide Metabolites (Nitrite and Nitrate) Level (Total Nox) in Nasal Smears

The samples were collected from all patients from the mucous membrane of the medial surface of both inferior turbinates with insertion for 30 seconds of absorbent paper strips, which were placed in separate tubes. Before measurement of the metabolites (nitrite and nitrate) level, the paper strips were placed into physiological saline for 3 minutes. The level of NOx in the saline samples was determined by a modified method by Miranda et al. using Griess Reagent. The absorbance was measured at 540 nm with a microplate reader (Multiscan GO, Thermo Fischer Scientific, and Finland). The standard curve for NaNO2 was used to calculate the metabolites (nitrite and nitrate) (total NOx) concentration in the samples [16].

Measurement of Total Antioxidant Activity (TAA) of Blood Serum

TAA was determined in deproteinized blood serum by using the 2.2-diphenyl-1-picryl-hydrazine (DPPH)-scavenging assay [17]. Serum samples (1 ml) were deproteinized by adding 3 ml of acetonitrile and centrifuging them for 10 min (4°C, 9500g). A supernatant was immediately collected and 1 ml was transferred to a tube, subsequently, 3 ml of DPPH was added, and the resultant solution's absorbance was read at 515 nm. A calibration curve was built with the use of Gallic acid, wherein the absorbance values were interpolated and the results were expressed as equivalents of Gallic acid (%).

Statistical Analysis

To compare the rank alterations, reflected in scores, of the subjective and objective characteristics of patients in groups I and II before and after treatment, the nonparametric Mann-Whitney U test was used. A P value of less than 0.05 indicated a statistically significant difference. Statistical significance of differences between nasal smear cytologic markers (eosinophil, neutrophil, lymphocyte counts, NO content), and blood plasma TAA levels was assessed using ANOVA (p< 0.05).

Results of Patients' Subjective and Objective (Instrumental) Examination

Table 2: Average number of subjective indicators in patients with VMR of groups I and II. (0 score - asymptomatic patient, 1 score - minor complaints, 2 scores - moderate complaints, 3 scores - strong, pronounced complaints (sneezing was assessed by intensity and duration).

*P<0.005 – the difference between studied parameters and the initial state

**p<0.005 – the difference in studied parameters between the groups

Table 3: Objective indicators of patients with VMR of groups I and II.

*P<0.005 – the difference between studied parameters and initial state

**p<0.005 – the difference in studied parameters between the groups.

Table 4: Statistical significance of the differences between the parameters of subjective and objective characteristics of I and II groups patients before the beginning and after the end of treatment (Mann-Whitney U Test).

In Tables 2 and 3, subjective and objective indicators of patients with VMR in groups I and II are presented before, on the 3rd and 5th days after the initiation of treatment, as well as at the end of the treatment. The study results indicate no statistically reliable difference in the insights of the objective and subjective indicators for groups I and II before the treatment (Table 2, 3, 4). At the same time, the positive results of treatment appear faster in patients of group II with VMR who have not undergone COVID-19; these patients showed an improvement in subjective and objective indicators already on the 5th day of treatment. On the 5th day of the treatment, subjective indicators of disease state sharply decreased (Table 2) and the dynamics of objective indicators were positive in 64% of patients with VMR from group II (Table 3); on the 10th day of treatment, positive dynamics were revealed in 78% of patients of group II. In group I patients with VMR who underwent COVID-19 more than 6 months ago, on the 5th day of treatment the positive dynamic was detected in 52% of patients, and on the 10th day - in 62% of patients. An important improvement in the ‘I’ group patients’ state was recorded only by the end of treatment. These data allow us to conclude that in patients with VMR on the phone of previous COVID-19 infection, it is necessary to increase the duration of the course of treatment.

Results of Nasal Smears Cytological Examination

Figure 1: An average number of the eosinophils (a), neutrophils (b), and leucocytes (c) in the nasal smears (1/50 HP) of patients of groups I and II with VMR before and after the treatment.

In Figure 1 results of the cytological examination of nasal smears of healthy volunteers, and patients of groups I and II with VMR before the beginning and after the treatment. The average number of eosinophils in nasal smears of healthy volunteers was 0±0,2, neutrophils - 1.5±0.5 and lymphocytes - 0±0,3; these data matched the normative values of inflammatory cells in the nasal smears of adults detected by Zhang Y. et al (2014) [18]. In nasal smears of patients with VMR of the group I mean eosinophils, lymphocytes, and neutrophils counts before the treatment were importantly higher than the respective insights in patients of the control group; in the II group mean eosinophil and lymphocytes counts were not different and neutrophils number was 4.4 times more than the respective insights in healthy volunteers. After treatment, the values of the studied indicators decreased significantly, however, in the patients of the first group, they still significantly exceeded the control level, while in the patients of the second group, and they approached the control.

Results of the Measurement of Total NOx Level

Figure 2 shows the results of the measurement of total NOx level in the nasal smears of healthy volunteers, and patients of groups I and II with VMR before the beginning and after the treatment.

Figure 2: Total NOx level in the nasal smears of healthy volunteers, and patients of groups I and II with VMR before the beginning (1) and after the treatment (2).

As seen in Figure 2, the level of NO in nasal smears of patients with VMR developed after more than 6 months of COVID-19 infection (group I) was 69%, and in patients with VMR who did not undergo COVID-19 (group II) - 189% of the level in healthy volunteers. After the treatment, the level of NO in both studied groups was changed towards the control insights (group 1: F = 1.35; p = 0.258; group 2: F = 12.01; p = 0.001).

Results of Measurement of Total Antioxidant Activity (TAA) of Blood Serum

Figure 3 shows the results of the measurement of TAA of blood serum of healthy volunteers, and patients of groups I and II with VMR before the beginning and after the treatment.

Figure 3: TAA level of blood serum of healthy volunteers, and patients of groups I and II with VMR before the beginning (1) and after the treatment (2) (calibration curve was built with the use of Gallic acid, wherein the absorbance values were interpolated and the results were expressed as equivalents of Gallic acid (%)).

As seen in Figure 3, the level of TAA in the blood serum of patients with VMR (groups I, and II) was lower than the level of TAA in the blood serum of healthy volunteers (by 66% and 31%, respectively). After the treatment level of TAA in both studied groups was increased (group 1: F = 2.43; p = 0.135; group 2: F = 1.15; p = 0.297), but in patients with VMR developed after more than 6 months of COVID-19 infection (group I), its level was statistically significantly lower than in control (F = 8,6; p = 0.001).

It has been reported that about 80% of hospitalized patients with COVID-19 for several months after discharge had long-term health complications, manifested by at least one symptom, particularly fatigue and dyspnea, disorders in the respiratory tract [3-6]. Despite numerous studies of patients with post-COVID complications, this clinical condition is not yet well understood and its biomarkers and their close association with various residual symptoms after recovery have not been established. The pathophysiology, risk factors, and management of post-COVID-19 are currently poorly understood. We studied indicators of inflammation and oxidative stress in the patients with VMR, who had COVID-19 more than 6 months ago (group I) and did not have COVID-19 (group II). Our study results show, that no statistically significant differences have been found between subjective characteristics and the values of objective indicators of instrumental examination in patients of groups I and II. Results of cytological examination show, that in the nasal smears of patients with VMR who had COVID-19 more than 6 months before (group I), eosinophils, lymphocytes, and neutrophils counts were importantly higher, and the level of NO in nasal smears of these patients was 64% lower than the respective insights in healthy volunteers. In nasal smears of patients without COVID-19 infection (group II) neutrophil number was 4.4 times higher, the level of NO was 31% lower, and mean eosinophil and lymphocyte counts were not different from the respective insights in healthy volunteers.

Vasomotor rhinitis is a term often used to describe rhinitis symptoms associated with non-allergic, non-infectious triggers with no clear etiology after the conclusion of an exhaustive search for a diagnosis. The pathophysiology of non-allergic rhinitis is complex, with still much to be discovered. The disease is characterized by heterogeneity in the clinical phenotypes and inflammatory profile [19]. VMR diagnosis is often made by exclusion according to any features of allergy in the nasal cytology (eosinophils) and the nasal allergen provocation test [20,21]. Hence, more studies and reliable biomarkers are needed to identify the VMR endotype accurately.

As follows from the results of the cytological examination of nasal smears of patients with VMR who had COVID-19 more than 6 months before, eosinophils, lymphocytes, and an increased number of neutrophils were revealed compared to corresponding indicators in patients with VMR without COVID-19. These data suggest that the pathogenesis of the VMR developed after COVID-19 infection likely includes the nonspecific release of histamine and chronic eosinophilic inflammation [22]. Sustained inflammation contributes to the systemic hyper inflammatory state and hyper-coagulopathy which are cardinal pathological mechanisms of severe stages of viral infection and in the development and progression of further complications by disrupting tissue (via autoantibodies), blood flow (e.g. immune thrombosis) and neurotransmitter metabolism (e.g. excitotoxicity) [23].

Investigations have shown that in the pathogenesis of COVID-19 infection, oxidative stress (an imbalance between the production and accumulation of cellular reactive oxygen species (ROS) and antioxidant defense) plays a significant role, that may lead to DNA mutations, injury to the mitochondrial respiratory chain, modifications of membrane permeability, and inactivation of the antioxidant defense systems [24,25]. After a viral infection, the body may experience prolonged inflammation, reduced antioxidant defense, and increased oxidative stress. This can trigger long-lasting anti-inflammatory processes, reducing the inflammatory state, restoring immune and oxidative balance, and preventing multiple organ dysfunction. If this compensatory reaction is insufficient, oxidative stress and inflammation usually reinforce each other, contributing to the systemic hyper inflammatory state, which has a wide variety of organ involvement and causes many symptoms, known as post-COVID-19 symptoms. Although studies examining the pathophysiology of the post-COVID-19 syndrome are still relatively few, there is growing evidence that this is a complex and multifactorial syndrome involving virus-specific pathophysiological variations that include many mechanisms, specifically oxidative stress, immune dysfunction, and persistent inflammation [23-25]. In this regard, it is important to assess the contribution of inflammatory and oxidative processes to cellular and tissue damage mechanisms during various post-COVID-19 complications.

According to the results of our studies. level of TAA in the blood serum of patients with VMR (groups I, II) was lower than the blood serum TAA level in healthy volunteers, this decrease was especially significant in patients with VMR developed about 6 months after COVID-19 infection (66% compared to control); these data indicate that oxidative stress in patients with VMR earlier exposed to COVID-19 infection is especially high and its important role in the pathogenesis of post-COVID-19 VMR. The intensive release of oxygen free radicals can cause epithelial damage and induce both the lower and nasal airway hyper responsiveness [26], contributing to the release of histamine and the development of eosinophilic inflammation in patients earlier exposed to COVID-19 infection. At the same time, the level of NO in nasal smears of patients with VMR developed after more than 6 months of COVID-19 infection (group I) decreased (was 69% of the level in healthy volunteers) and in patients with VMR, who did not undergo COVID-19 (group II) importantly increased (was 189% of the level in healthy volunteers) in comparison to control level. Nitric oxide (NO) is an important mediator of the various biological processes, which participate in managing the body's immune and inflammatory responses [27-29]. All three isoforms of NO-synthase (NOS) (constitutive - endothelial (eNOS) and neuronal (nNOS), and inducible (iNOS)) are presented in the human nasal mucosa [30]. The majority of NOS in the human nasal airway is associated with the nasal epithelium. Nitric oxide can act as a scavenger of oxygen-free radicals, including superoxide [30]. Therefore, the production of basal levels of NO, by the epithelium, could represent a defensive mechanism and decrease the susceptibility of the epithelium to oxidative damage, resulting in hyper responsiveness [30]. In a hyper-inflammation state, oxidative stress conditions increase iNOS expression and a rise in NO production is possible. Excess NO readily reacts with the superoxide anion to form cytotoxic peroxynitrite; this induces epithelial cell damage, and nasal airway hyper responsiveness and increases the severity of VMR. The clinical studies confirm that the NO content in the upper and lower respiratory tract is a validated marker of airway inflammation [26].

Therefore, a basal level of NO production may be protective against airway hyper responsiveness, excessive NO release, possibly mediated by an up regulation of iNOS during chronic inflammation, may be destructive and cause airway hyper responsiveness. It is established that the nasal NO level is significantly higher in patients with allergic rhinitis compared to healthy people, while in patients with non-allergic VMR, it was significantly lower (especially in patients with VMR who showed eosinophilia in nasal swabs) [29]. Nasal NO can be identified as a diagnostic marker of patients previously exposed to COVID-19 infection and without it. Based on the results of the study, we can conclude that the pathogenesis of VMR of a patient previously exposed to COVID-19 infection is characterized by especially high oxidative stress intensity, inducing depletion of TAA in the body, oxidative degradation of NO, lowering of nasal NO content, causing the abolishment of its protective ability against airway hyper responsiveness and development the chronic eosinophilic inflammation. For VMR treatment, we used local intranasal antihistamine spray, reducing the effects of the inflammatory mediators (bradykinin, serotonin, histamine, leukotrienes) in the body.

The results of our study indicate a positive effect of the treatment with intranasal antihistamine spray in patients with VMR (groups I and II). At the same time, it should be noted that positive treatment results are detected faster in patients with VMR who have not undergone COVID-19 infection (group II). These patients showed an improvement in subjective and objective parameters already on the 5th day of treatment - subjective indicators sharply decreased in 64% of patients, the dynamics of objective indicators were positive and on day 10 of the treatment, their normalization was observed in 78% of patients. In patients with VMR who had COVID-19 at least 6 months ago (group I) on the 5th day of treatment, positive dynamics were detected in 52%, and on day 10 - in 62% of patients. After the treatment in patients of both studied groups, TAA increased (especially in group I), and the level of NO changed towards the control insights (that indicates the decrease of oxidative degradation of nitric oxide and restoring its protective effect against airway hyper responsiveness}. Accordingly, at the end of the treatment mean eosinophils, lymphocytes, and neutrophils counts in nasal smears of patients with VMR decreased significantly and in group II approached the control level, however, in patients with VMR previously exposed to COVID-19 infection (group I) still importantly exceeded the control level. Based on the results of our studies, the proposed treatment regimen with the local intranasal antihistamine spray can be recommended for patients with vasomotor rhinitis, both with and without COVID-19 infection. The study results indicate that patients with VMR who had previous COVID-19 infection may require an extended treatment course.

In patients previously exposed to COVID-19, VMR infection intensity of the oxidative stress and depletion of nasal NO were especially high, causing the abolishment of protective ability, chronic eosinophilic inflammation, and airway hyper responsiveness. Intranasal antihistamine spray is effective for VMR treatment in groups I and II. In patients with VMR who previously had COVID-19 infection, it is necessary to increase the treatment course duration.

Disclosure

The authors do not have any conflicts of interest or financial support related to this work.

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