Effect of topical anticholinergic medication on clinical manifestations control among patients with vasomotor rhinitis versus allergic rhinitis: as comparative clinical trials

Abstract

Background

The use of a topical anticholinergic medication, ipratropium bromide, and its ability to inhibit methacholine and rhinitis-induced hypersecretion is emphasized. Ipratropium bromide appears to be both safe and effective in reducing this troublesome symptom. This study is designed to show the therapeutic effect of anticholinergic local treatment on nasal mucosa in patients with vasomotor rhinitis.

Objective

To assess the therapeutic effect of local anticholinergic treatment on nasal mucosa in patients with vasomotor rhinitis compared to non-vasomotor (allergic) patients and normal individuals, and if there any down regulation of the muscarinic receptors or not.

Patients and methods

This prospective intervention study was conducted in Otorhinolaryngology Department, Faculty of Medicine, Ain Shams University. This study was conducted on 60 cases. All patients were divided into 3 groups: study group (1) includes 20 patients diagnosed clinically non-allergic rhinitis suggestive to be vasomotor rhinitis. Study group (2) includes 20 patients diagnosed as allergic rhinitis. Study group (3) includes 20 patients performing surgery for non-vasomotor rhinitis non-allergic causes (as septoplasty or rhinoplasty).

Results

Comparison between the pre- and post-SNOT questionnaire of symptoms among vasomotor group showed that there was a significant difference between the pre- and post-treatment SNOT questionnaire symptoms; nasal obstruction, runny nose, post-nasal drip, thick nasal discharge and Lack of good night sleep. Among allergic cases group, there was a significant difference between the pre- and post-treatment IHC (immunohistochemistry) findings considering Epithelium, Glands, arteries and veins. 20% of cases had grade 3 epithelium before treatment while after treatment, this was dropped to 0%. Comparison between the pre- and post-SNOT questionnaire of symptoms among allergic group showed that there was a significant difference between the pre- and post-treatment SNOT questionnaire symptoms; runny nose, post-nasal drip, and thick nasal discharge. Among non-vasomotor rhinitis non-allergic causes (as septoplasty or rhinoplasty) group, there was a significant difference between the pre- and post-treatment IHC findings considering epithelium, glands, and arteries; however, no significant difference between the pre- and post-IHC veins grade. Also, there was no significant difference between the pre- and post-treatment SNOT questionnaire symptoms.

Conclusion

Topical anticholinergics such as ipratropium bromide nasal spray are effective in treating rhinorrhea symptoms in allergic and non-allergic rhinitis. Further controlled studies with larger sample size and longer follow-up are needed to confirm our results and to identify risk factors of adverse events.

Background

Vasomotor rhinitis is a non-infectious non-allergic disease, which is characterized by nasal hyper reactivity resulting in symptoms of nasal obstruction, rhinorrhea, and sneezing, which are often indistinguishable from nasal symptoms of allergic rhinitis. Diagnosis of Vasomotor rhinitis is established on the basis of persistent symptoms all over the year after exclusion of infection, any medical or anatomical disorder of the nose, and negative skin prick test for IgE‐mediated hypersensitivity to relevant aeroallergens [1].

Acetylcholine from post-ganglionic nerve-endings has an important role in pathophysiology. There are five subtypes of muscarinic receptor, labeled M1 to M5. M1, M2, and M3 receptors are found on glands, epithelium, veins, and arteries. M4 receptors are found on arteries, and M5 receptors are found on arteries and glands. M3 subtype is the most common one [2]. M1, M3, and M5 subtypes couple to the inositol polyphosphate, while M2 and M4 subtypes inhibit the production of cAMP [3].

Anticholinergic drugs are consequently useful in treating rhinorrhea in patients with rhinitis. The effectiveness and tolerability profiles were demonstrated in clinical trials, both in long-term treatment [4] and within the prevention of excessive rhinorrhea induced by methacholine [5]. Additionally, the intranasal ipratropium bromide provides good relief of rhinorrhea in the common cold [6]. Recently, a new preparation nasal spray of ipratropium bromide, a solution delivered by a metered pump, has been developed without the usage of potentially ozone-depleting propellants. The aim of that study was to assess whether pretreatment with intranasal ipratropium bromide aqueous spray could prevent the rhinorrhea of vasomotor rhinitis.

Aim of the work

This study is designed to assess the therapeutic effect of local anticholinergic treatment on nasal mucosa in patients with vasomotor rhinitis compared to non-vasomotor (allergic) patients and normal individuals, and if there any upregulation of the muscarinic receptors or not.

Patients and methods

Type of study

Prospective intervention study

Study setting

Otorhinolaryngology Department, Faculty of Medicine, Ain Shams University.

Study population

Inclusion criteria

All adult patients with vasomotor rhinitis and allergic rhinitis and control group from 18 to 50 years old.

Exclusion criteria

Acute sinusitis. Invasive acute or chronic fungal sinusitis. Chronic granulomatous inflammations. Use of oral or nasal steroids for at least 2 months. Hypertensive patients. Ischemic heart diseases. Local decongestant agents’ abuser.

Sampling method

The current study consists of study group (1), which includes 20 patients diagnosed clinically non-allergic rhinitis suggestive to be vasomotor rhinitis. Study group (2) includes 20 patients diagnosed as allergic rhinitis. Study group (3) includes 20 patients performing surgery for non-vasomotor rhinitis non-allergic causes.

Ethical considerations

All patients will be subjected to the following protocol after taking their written consent. approved by an ethical committee before the start of the recruitment (FMASU M D 406/2019).

Study procedures

All patients will be subjected to the following protocol. Full history taking (allergy history, asthma, aspirin sensitivity, and tobacco use) with emphasis on vasomotor rhinitis symptoms. Total IgE levels to suggest symptoms. Otorhinolaryngological examination and endoscopic examination of the nasal cavity to exclude comorbidities. Biopsy will be obtained from mucosa of inferior turbinate of these patient before any medical treatment under local anesthesia at outpatient clinic. Another biopsy will be obtained from the same patient under general anesthesia after 3 months of local anticholinergic treatment as atrovent (ipratropium bromide) Nasal spray 0.06% 42 mcg/spray with dose of two sprays (84 mcg) per nostril three times daily. Nasal symptomatology will be assessed using the standardized SNOT 22 evaluation score. Nasal tissues collected then embedded in paraffin will be cut into sections. Hematoxylin-eosin (HE) staining is routinely performed for histological examination, and then IHC staining will be performed using muscarinic acetylcholine receptor antibody from Abbexa Ltd., as an objective assessment pre- and post-medical ttt and divided into semi quantitative scores for staining of muscarinic receptor in human inferior turbinate mucosa into grade 0 negative, grade 1 recognizably positive, grade 2 clearly positive, and grade 3 excessively positive.

Data management and analysis

The collected data was reviewed, coded, arranged, and introduced to a PC using Statistical package for the Social Science (IBM Corp., Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.). The data was presented and appropriate analysis was done along with the type of data gained for each parameter.

Descriptive statistics

Shapiro-Wilk’s test was used to evaluate normal distribution of continuous data. Mean, standard deviation (±SD), and range was used for parametric numerical data. Frequency and percentage of non-numerical data.

Analytical statistics

ANOVA test was used to assess the statistical significance of the difference between more than two study group means. Chi-square test that was used to examine the association between two qualitative variables. Fisher’s exact test was used to examine the relationship between two qualitative variables when the expected count is less than 5 in more than 20% of cells. Wilcoxon signed rank test used to assess statistical significance of the alteration of an ordinal variable (score) measured two times for the same study group. McNemar test was used to assess the significance of the alteration between the qualitative variable that measured two times in the same study group. P value was used to determine the level of significance: P > 0.05: non-significant (NS), P < 0.05: significant (S), and P < 0.01: highly significant (HS).

Results

This study enrolled three groups:

• Group 1 (vasomotor group)

• Group 2 (allergic group)

• Group 3 (control group)

Discussion

Chronic rhinitis is persistent inflammation of the mucosa of the nasal cavity and is clinically classified to non-allergic, allergic, or mixed (both allergic and non-allergic triggers) etiologies [7]. Trademark symptoms of rhinitis include nasal blockage or congestion, nasal discharge (anterior and/or posterior), facial pain or facial pressure, and dysosmia [8].

Allergic rhinitis (AR), is the most common and recognizable phenotype, which linked to an immunoglobulin E-mediated inflammatory response resulting in swelling and hyperreactivity of the mucosa [9]. Non-allergic rhinitis (NAR) is a mixed collection of distinct pathophysiological subtypes causing rhinologic symptoms, in the absence of allergic inductions [10].

Muscarinic or acetylcholine receptors play a significant role in glandular secretion and vasomotor dilation to blood vessels in the human nasal mucosa [11]. Anticholinergics serve to inhibit the binding of acetylcholine, thus preventing downstream cholinergic activation of the parasympathetic mucosal secretion and inflammation. Intranasal anticholinergic sprays lately became more and more investigated therapy for potential mucin-reducing effects on the mucosa in chronic rhinitis patients. Blockage of these muscarinic pathways play a key role in the reduction of the clinical symptoms such as rhinorrhea [12]. Current treatment strategies for chronic rhinitis include a significant role for topical anticholinergics that is symptom-specific and adjunctive [13, 14].

Regarding the demographic data of the studied groups, we found that there were no statistically significant differences between the vasomotor, allergic and control groups as regards age and sex.

Comparison between the three study groups as regards IHC data before treatment, showed that there was a significant difference between the three study groups as regards pretreatment IHC findings considering epithelium, glands, and vein; however no significant difference was found regarding arteries. Sixty percent of vasomotor group had grade 3 Epithelium compared to 20% and 0% of allergic and control groups respectively. Similarly, 40% of vasomotor group had grade 3 glands compared to 20% and 0% of allergic and control groups respectively. As regards veins, 10% of each of vasomotor and allergic groups had grade 3 veins compared to 0% of control group. Also, Comparison between the 3 study groups as regards IHC data after treatment showed that there was a significant difference between the 3 study groups as regards post-treatment IHC findings considering epithelium, glands, and vein; however, no significant difference was found regarding arteries.

The current study showed that the best improvements in epithelium and veins were found in allergic group followed by vasomotor group while the best improvement in glands was found in vasomotor group followed by allergic group. Improvement in arteries was similar in vasomotor and allergic groups. Minimal or no improvement was found in control group.

Comparison between the three study groups as regards SNOT questionnaire before treatment showed that there was a significant difference between the three study groups as regards pretreatment SNOT questionnaire. Also, there was a significant difference between the three study groups as regards post-treatment SNOT questionnaire except for runny nose, post-nasal drip, and thick nasal discharge.

Comparison between the 3 study groups as regards improvement in SNOT questionnaire after treatment showed that there was a significant difference between the three study groups as regards improvement in SNOT questionnaire in 5 symptoms; nasal obstruction, running nose, post-nasal drip, thick nasal discharge, and night sleep.

The present study showed that there were comparable improvement in SNOT questionnaire was found in vasomotor and allergic groups. However, almost no improvement was found in control group.

To the best of our knowledge, there were no studies in literature have compared the efficacy of topical anticholinergic on vasomotor, allergic, and control groups. However, there were several studies have assessed the efficacy of this treatment in each group separately.

Among vasomotor group the current study showed that there was a significant difference between the pre- and post-treatment IHC findings considering epithelium, glands, arteries, and veins. Sixty percent of cases had grade 3 epithelium before treatment while after treatment, this was dropped to 20% only.

Comparison between the pre- and post-SNOT questionnaire of symptoms among vasomotor group showed that there was a significant difference between the pre- and post-treatment SNOT questionnaire symptoms; nasal obstruction, runny nose, post-nasal drip, thick nasal discharge, and lack of good night sleep.

In agreement with our results, [15] studied the long-term safety and success of ipratropium bromide spray 0.03% in the treatment of non-allergic rhinitis, and they enrolled 285 patients. The study revealed that ipratropium bromide was good tolerated without serious side effects in these patients.

Also, [16] assessed the new isotonic aqueous ipratropium bromide nasal spray pump, precisely in patients with non-allergic rhinitis. Two hundred thirty-three patients shared in an 8-week double-blind parallel evaluation of ipratropium bromide nasal spray with a saline solution. Treatment with the ipratropium spray resulted in a 30% reduction in rhinorrhea; this reduction was greater than that seen with the saline vehicle. There was a modest reduction in post-nasal drip, sneezing, and congestion with both treatments, which may be attributable to the salutary results of the saline solution.

Also, [17] compared the value and safety of the combined use of ipratropium bromide nasal spray 0.03% (42 microg per nostril tid) and beclomethasone dipropionate nasal spray (84 microg per nostril bid) against that of either active agent alone for the treatment of rhinorrhea. The study enrolled 533 patients with perennial rhinitis (279 allergic and 274 non-allergic). The study decided that the combined use of the ipratropium bromide nasal spray with beclomethasone dipropionate nasal spray is more effective than either active agent for the treatment of rhinorrhea, and does not result in a potentiation of adverse drug reactions. Ipratropium bromide nasal spray 0.03% alone should be considered in patients for whom rhinorrhea is the primary symptom, and its use in combination with a nasal steroid should be considered in patients where rhinorrhea is one of the chief symptoms, or in patients with rhinorrhea not completely responsive to other therapy.

Finally, our results supported by the recent systematic review by [18] aimed to assess the safety and efficiency of anticholinergic nasal sprays in managing of allergic and non-allergic rhinitis regarding symptom severity and duration, The study included 12 studies (n = 2024 patients). And anticholinergic treatment was demonstrated to significantly reduce rhinorrhea severity and duration in allergic and non-allergic rhinitis patients (Figs. 1, 2, 3, 4, 5, 6, 7, 8, and 9; Tables 1 and 2).

Fig. 1

Comparison between the pre- and post-IHC data among vasomotor cases study groups

Fig. 2

A case of vasomotor rhinitis pre- and post-treatment with immunohistochemical staining show staining of arteries grade 3 to grade 0

Fig. 3

Comparison between the pre- and post-SNOT questionnaire of symptoms among vasomotor group

Fig. 4

Comparison between the pre- and post-IHC data among allergic cases study groups

Fig. 5

Comparison between the pre- and post-IHC data among control group

Fig. 6

Comparison between the 3 study groups as regards IHC data before treatment

Fig. 7

Comparison between the 3 study groups as regards IHC data after treatment

Fig. 8

Comparison between the 3 study groups as regards improvement in IHC data after treatment

Fig. 9

Comparison between the 3 study groups as regards improvement in SNOT questionnaire after treatment

Table 1 Comparison between the pre- and post-SNOT questionnaire of symptoms among allergic group

Table 2 Comparison between the pre- and post-SNOT questionnaire of symptoms among control group

Conclusion

Topical anticholinergics such as ipratropium bromide nasal spray are effective in treating wet symptoms as rhinorrhea in allergic and non-allergic rhinitis. Further controlled studies with larger sample size and longer follow-up are needed to confirm our results and to identify risk factors of adverse events.