Non-allergic cell-mediated vasomotor rhinitis.

NAR (Non Allergic Rhynitis) – Non Allergic Rhinitis

Nonallergic vasomotor rhinitis, among chronic rhinopathies, represents an area for which the diagnostic and therapeutic approach is not unambiguous. Most often, this type of rhinitis has no specific diagnosis and is classified as “nonspecific vasomotor rhinitis” or “idiopathic.”

NARs are characterized by intense pseudo-allergic symptoms, such as nasal obstruction, itching, sneezing blanks, burning of the nasal mucous membranes, rhinorrhea; and can be confused with IgE-mediated rhinitis. They also exhibit nonspecific reactivity, manifesting symptoms from a variety of stimuli, such as temperature changes, cold air, intense perfumes, tobacco smoke, nasal irrigations, and topical drug treatments. It happens that subjects practicing swimming in the pool are forced to abandon the sport activity due to the appearance of nasal hyperreactivity (sneezing, obstruction and nasal burning) resulting from contact of the nasal mucosa with chlorinated water. These individuals complain of nasal obstruction, often basal, which is accentuated during sleep to the point of snoring and mouth breathing, and they experience easy irritability of the nasal mucosa, evoked by nonspecific stimuli.

An anamnestic finding characteristic of NAR is the high number of specialist visits to which parents, seeking a definitive diagnosis, refer the pediatric patient. In fact, NARs are hardly framed by the specialist during the first visit, especially if he or she does not resort to effective diagnostic-instrumental investigations for rhinoallergological diagnosis: prick test, endoscopy, nasal cytology, rhino-manometry, and diagnostic kits for specific nasal provocation tests. Since these are cell-based diseases, the diagnostic “gold standard” is cytological examination of the nasal mucosa.

NARs have a significant burden, both in terms of health care expenditures and in terms of social and quality-of-life losses, due to intense and persistent nasal symptoms, along with a tendency to associate with more important diseases such as bronchial asthma, ASA sensitivity, rhino-bronchial syndrome, sinusopathy, and nasal polyposis in adults.

The group of nonallergic or “cellular” vasomotor rhinitis includes NARNE (Non Allergic Rhinitis whit Neutrophils), NARES (Non Allergic Rhinitis with Eosinophils), NARMA (Non Allergic Rhinitis whit Mast cells) and finally NARESMA (Non Allergic Rhinitis with Eosinophils and Mast cells).

NARNE

NARNE is characterized by a major infiltration of neutrophils into the mucosa (>of 50%). Unlike infectious rhinitis, along with neutrophils, no infectious agents are found in the mucosa. The frequency of this rhinopathy, particularly in adults, is increasing; as those most affected are workers in industry, handicrafts, and residents of industrialized centers, as well as chronic smokers; the increase is probably due to living in environments containing significant airborne concentrations of agents aggressive to the nasal mucosa.

With the release of chemical mediators (particularly neutrophil elastase), neutrophils are the main cause of free radical formation in the mucosa, and the consequent suffering of the mucosal epithelium, which results clinically in the appearance of certain symptoms such as catarrhal rhinorrhea, burning, and nasal congestion.

Unlike the other cellular vasomotor forms, the symptomatology of NARNE is less intense, and may regress once the pathogenic cause is identified and removed.

In the context of chronic rhinopathies, the picture concerning neutrophils is specific to forms that are accompanied by cystic fibrosis and anthro-coanal polyp.

NARES

NARES is a non IgE-mediated vasomotor rhinitis characterized by eosinophilic infiltration of the nasal mucosa, which usually reaches rather high rates (50-70%). The pathophysiology of NARES, as well as for other “cellular” forms, remains unknown to this day. As with NARMA and NARESMA it is often accompanied by nasal polyposis, and/or asthma and/or ASA sensitivity. In a percentage of patients, nasal eosinophilia is accompanied by blood hyper-eosinophilia. Sometimes, these forms of rhinitis can recruit mast cells for reasons as yet unknown, transforming, in fact, into eosinophil-mastocytic forms (NARESMA), where the symptomatology also becomes more intense and continuous.

NARMA

NARMA is characterized by the presence of mast cells, partly degranulated, in the nasal mucosa. The clinical and symptomatic picture is very intense (nasal obstruction, rhinorrhea, blanks sneezing, and itching), and is often associated with asthma and/or naso-sinus polyposis. Like NARES, it may represent forms of transition to NARESMA.

NARESMA

NARESMA is a recently described nosological entity. The most important aspect of NARESMA is that, unlike the other forms, it is more frequently associated with nasal polyposis, asthma, and sinusitis; it is also associated with a worse quality of life, with sleep disturbances (continuous awakenings, snoring, and sleep-apnea). When associated with nasal polyposis, it constitutes a poorer prognostic index of recurrence.

NARESMA, like NARES and NARMA, responds very well to corticosteroid therapy, both topical and systemic, and, as with all vasomotor rhinopathies, needs close clinical and cytologic monitoring over time.

These rhinitis are chronic conditions, and they require ongoing therapies over time and individualized follow-ups to control symptoms and prevent complications.

“Overlapping” rhinitis

The most important contribution that nasal cytology has made in the field of rhinopathy diagnostics is that it has introduced the concept of “overlapping” multiple nasal pathologies; it is, in fact, possible, thanks to it, to identify multiple nosological entities in patients (for example: allergic rhinitis and NARES, or allergic rhinitis associated with NARESMA).

Being able to make the specific diagnosis, allows optimization of therapy. Typically, these are patients who have only seasonal allergen positivity but present with perennial rhinitic symptoms, with positive cytology for eosinophils and/or mast cells. Rhinocytopathological study is, in these cases, crucial, as it allows the diagnosis of overlapping multiple nasal pathologies.

“Overlapping” rhinitis shows a more intense vasomotor symptomatology, with a chronic course; if not diagnosed and treated properly, it tends to complicate, with hypertrophy of the turbinates, rhinosinusitis, rhino-bronchial syndrome, and, after some years, nasal polyposis.

In allergology, the diagnosis of overlapping forms is very important. Patients, when subjected to specific immunotherapy, on the one hand derive all the benefits associated with the therapy (blocking the so-called “allergic march” and the course toward polysensitization), and on the other hand do not show relevant improvements in symptomatology, as the concomitant “nonallergic” form does not respond to the immuno-specific treatment. Therefore, additional drug treatment is required to recover.

Current therapeutic possibilities

Although various environmental factors, including exposure to ozone and some respiratory viruses, are capable of causing damage to the respiratory mucosal epithelium, there are many data regarding the role of eosinophils as a major cause of desquamative-type injury effects on the respiratory epithelium. The infiltration of eosinophils into the airway mucosa is characteristic not only of allergic forms of rhinitis, but also of nonallergic forms (NARES, NARESMA), where such cellular components are even higher percentages than in allergic rhinopathies themselves.

Eosinophils, once activated, degranulate, releasing their enzyme products. Immunohistochemical studies demonstrated a deposition of eosinophilic Major Basic Protein (MBP) on the respiratory epithelium, precisely at the most damaged areas. Other studies have shown that at the concentration of 10mcg/ml, MBP causes desquamation of epithelium explants in vitro, while at lower concentrations it can alter ion transport processes and cause ciliostasis. Sputum samples obtained from asthma patients have been shown to contain 0.3 to 93 mcg/ml of MPB, thus indicating that cytotoxic levels of this protein are achieved in vivo. Of the importance of eosinophil in causing epithelial damage has been confirmed by a number of histological studies performed on patients with eosinophilic infiltrating diseases (allergic rhinitis, NARES, NARESMA, nasal polyposis). In all histological sections there were pictures of interrupted and/or disepithelialized respiratory epithelium in sections.

The MBP released by eosinophils is mainly responsible for the lysis of intercellular junctional apparatuses; this results in the opening, to a greater or lesser extent, of gaps. This condition results in the loss of one of the main functions of the mucosal epithelium: that of barrier, the consequence of which is the direct contact of chemical-physical-atmospheric and infectious agents with the tonaca propria of the mucosa, within which the Trigeminal Irritant Receptors are located. Direct stimulation of trigeminal receptors underlies the vasomotor symptoms, itching, sneezing blanks, rhinorrhea, and nasal congestion that characterize rhinopathies with eosinophilic infiltration.

Thus, the use of drugs with specific action on the immunophlogistic component finds an important therapeutic rationale. Studies have shown that corticosteroid treatment, in addition to reducing the inflammatory cell infiltrate, restores epithelial integrity, resulting in reduced hyperresponsiveness. Moreover, the therapeutic action of corticosteroids in restoring barrier integrity has historically been considered less important than the specific activity against immunophlogistic cells, proinflammatory cytokines, and adhesion molecules.

The mechanism of action of nasal steroid in reducing eosinophilic infiltrate is known. The corticosteroid penetrates the interior of the cells where it binds to a specific receptor and, once it reaches the nucleus, interferes with factors responsible for RNAm transcription for cytokines, chemokines, enzymes, and adhesion molecules and proteins involved in inflammatory processes, synthesized by immune cells. This results in a reduction in the progression of the inflammatory cascade by decreasing the recall of inflammatory cells, reducing the concentration of cytokines and chemokines, and reducing fibroblast proliferation and synthesis of extracellular matrix proteins. Corticosteroids have also been shown to reduce the release of preformed mediators such as prostaglandins, and leukotrienes; as well as inhibit histamine release. These pharmacological effects result in a reduction in the symptomatology of rhinitis, and in particular nasal congestion.

Within the corticosteroids used in respiratory diseases, mometasone furoate has been shown to have the lowest systemic absorption, the highest affinity for tissue receptors, and the best anti-inflammatory activity. Mometasone furoate has been shown to significantly reduce eosinophils, as early as 6.5 hours after administration, in patients with seasonal allergic rhinitis.

Pharmaceutical product under study

The result of NAR is diffuse remodeling of the respiratory mucosa, resulting in the feeding of the inflammatory process with the continued degranulation and proliferation of mast cell.

Corticosteroids have been shown to interfere directly with the inflammatory process by inhibiting the hyperreactivity of neutrophil, eosinophilic, and/or mast cells for a long time, while there is no definitive certainty that they have an effect on respiratory mucosal remodeling.

In the presence of NAR (NARNE, NARES, NARMA AND NARESMA), a large number of neutrophils, mast cells and/or eosinophils proliferate at the level of the nasal mucosa; these cells then release in excess substances that damage the respiratory mucosa, triggering a vicious circle that leads to increased expression of rhinopathy symptoms, chronicity of the inflammatory process, and increased possibility of adhesion and penetration of any pathogenic microorganisms.

The investigational product is indicated to exert a protective action on mast cells of the respiratory mucosa, reducing their reactivity while decreasing the chemotactic recruitment of eosinophils and neutrophils.

It will also exert a protective action on the mucosa by promoting tissue repair.

Given the study phases that have already been completed, side effects from the use of this product, as well as risks of overdose or interactions with other medicines, appear unlikely.

With the use of the investigational product, rapid reduction of symptoms (sneezing blanks, burning, itching, rhinorrhea) without metabolic and toxic burden on the body, and stabilization of the chronic condition over long periods is expected.