Nonallergic Rhinitis: Definition, Classification, and Management
Summary
Chronic rhinitis can be classified roughly as allergic, infectious, or nonallergic, noninfectious. It is estimated that 50% of cases of chronic rhinitis is nonallergic. The differential diagnosis of nonallergic, noninfectious rhinitis is extensive. An important subgroup of nonallergic rhinitis is idiopathic rhinitis, formerly called vasomotor rhinitis. Research on the underlying pathophysiology of nonallergic rhinitis has moved from autonomic neural imbalance to inflammatory disorders (local allergy), the nonadrenergic, noncholinergic (NANC) peptidergic neural system, and central neural hyperesthesia, still without convincing proof. The patient history is the most important part of the diagnosis of non-allergic rhinitis. Asking for trigger factors that provoke symptoms, such as physical and chemical stimuli, strong emotions, alcoholic beverages, changes in hormone levels (menstrual period), certain medications, and occupations, can lead to a solution for the problem. There are several available therapies for nonallergic rhinitis, both surgical and pharmacotherapeutic, all claiming partial success. With the exception of rhinitis in the elderly, where ipratropium bromide is the first treatment of choice, there is no obvious best treatment in nonallergic rhinitis.
Introduction
Rhinitis is a very common disorder. Most people suffer from infectious rhinitis at least once a year. It generally proves to be a self-limiting disease, disappearing in 1 or 2 weeks without specific treatment. This in contrast to chronic rhinitis, affecting up to 20% of the general population.1
Chronic rhinitis can be due to common factors, such as mechanical obstruction, allergy, and smoking, or less common factors, such as xylometazoline abuse and cystic fibrosis. Rhinitis refers to inflammation of the nasal mucosal membrane. However, markers of inflammation are not examined in routine clinical work. Therefore, the term rhinitis in daily practice is used for nasal dysfunction causing such symptoms as nasal itching, sneezing, rhinorrhea, and nasal blockage.
Definition and Differential Diagnosis
Rhinitis Classification
Chronic rhinitis can roughly be classified as allergic, infectious, or nonallergic, noninfectious.1 The exact figures are unknown, but most ear, nose, and throat (ENT) clinics report a 50–50 division between allergic and nonallergic patients in perennial rhinitis.2
Note
Roughly half of all patients with perennial noninfectious rhinitis suffer from allergy, with the remaining half diagnosed with nonallergic rhinitis.
Allergic rhinitis is clinically defined as a symptomatic disorder of the nose induced by an immunoglobulin E (IgE)–mediated inflammation after allergen exposure of the nasal mucosa. The diagnosis of allergy is based on diagnostic tests for allergy, such as skin prick tests and measurement of serum-specific IgE.
The disease is nonallergic when allergy has not been proven by proper allergy examination (patient history, skin prick testing, and measurement of serum-specific IgE antibodies).
Rhinitis is considered noninfectious when the nasal discharge is clear and watery, not purulent. Detection of microorganisms (viruses, bacteria, and fungi) is generally not used as a diagnostic criterion.3
When allergy and infections have been excluded as the cause of rhinitis, several poorly defined nasal conditions of partly unknown etiology and pathophysiology remain. The differential diagnosis of nonallergic, noninfectious rhinitis is extensive:
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The mechanisms have been only partly determined.
Nonallergic Noninfectious Perennial Rhinitis
Nonallergic, noninfectious perennial rhinitis can be divided into disorders with known and unknown pathology.
Occupational Nonallergic Rhinitis
Occupational rhinitis arises in response to an airborne agent present in the workplace. Many occupational agents are irritants, and nonallergic hyperresponsiveness may occur.
Most agents inducing occupational nonallergic rhinitis are small molecular weight compounds, such as isocyanates, aldehydes, ninhydrin, and pharmaceutical compounds.4,5 More than 250 different chemical entities have been identified. Although these can act as reactive haptens, nonimmunologic mechanisms are common.
Some compounds, such as chlorine, can induce irritant rhinitis in 30 to 50% of exposed workers.
Drug-induced Rhinitis
Rhinitis Medicamentosa
Long-term use of topical nasal vasoconstrictors (e.g., xylometazoline hydrochloride and other α-adrenergic receptor agonists) often results in rhinitis medicamentosa with possible histologic mucosal changes and drug dependence. Rhinitis medicamentosa can be defined as a condition of nasal hyperreactivity, mucosal swelling, rebound nasal congestion, and tolerance that is induced, or aggravated, by the overuse of topical vasoconstrictors.6 In countries such as the Netherlands and the United Kingdom, where decongestants have long been available as over-the-counter medications, the condition is commonly encountered. Generally, these patients can be adequately treated by lucid exposition, vasoconstrictor withdrawal, and a topical corticosteroid spray and in very severe cases prednisone to alleviate the withdrawal process.7 After successful vasoconstrictor withdrawal, any remaining nasal disorder can be treated. It is not advisable to start treatment of an underlying disorder before 6 months of complete withdrawal of the vasoconstrictors because the mucosa that is severely damaged needs a considerable time to repair. However, we can assure our patients that full recovery occurs after withdrawal, even after long abuse.
Other Drugs Inducing Nonallergic Rhinitis
Several different types of medications are known to cause nasal symptoms. Reserpine, hydralazine, guanethidine, phentolamine, methyldopa, angiotensin-converting enzyme (ACE) inhibitors, β-blockers, chlorpromazine, aspirin, other nonsteroidal antiinflammatory drugs (NSAIDs), oral contraceptives, and α-adrenergic receptor antagonists such as prazosin have all been associated with nasal symptoms, as have intraocular ophthalmic preparations.2 Also, psychotropic agents such as thioridazine, chlordiazepoxide, amitriptyline, perphenazine, and alprazolam can have nasal side effects.8 It is important to always ask whether there is a time correlation between the start of symptoms and medication use.
Hormonal Rhinitis
Changes in the nose are known to occur during the menstrual cycle, puberty, and pregnancy and in specific endocrine disorders, such as hypothyroidism and acromegaly.8,9 Hormonal imbalance may also be responsible for the atrophic nasal change seen in postmenopausal women. Persistent hormonal rhinitis may develop during pregnancy in otherwise healthy women. Its severity parallels the blood estrogen level. The symptoms usually quickly disappear after delivery.
Rhinitis in the Elderly
Rhinitis in the elderly, or senile rhinitis, is a characteristic clinical picture of the elderly patient suffering from a persistent clear rhinorrhea without nasal obstruction or other nasal symptoms. Patients often complain of the classic drop on the tip of the nose. The first treatment option is intranasal ipratropium bromide (generally with good clinical result when given up to 6 times daily).10,11 It displays a parasympatholytic effect in topical use and antagonizes acetylcholine transport in efferent para-sympathetic nerves, thus decreasing submucosal gland secretion, which is the cause of hypersecretion. Another suggested treatment is the injection of botulinum toxin type A (BTA) into the nasal cavities.12 Recently, new evidence for an old treatment has surfaced. The technique of vidian neurectomy has been reassessed with the use of the endoscope and better understanding of the nasal and sinus anatomy.13,14 This treatment now seems to have excellent results, although long-term data are missing, and the treatment is not without potential serious side effects.15
Nonallergic Rhinitis with Eosinophilia Syndrome
NARES was originally described in 1981 by Jacobs et al.16 They described patients with perennial nasal symptoms—sneezing paroxysms, profuse watery rhinorrhea, and pruritus of the nasopharyngeal mucosa in an “on again, off again” pattern—with profound eosinophilia, as seen in a nasal smear (a nasal smear with > 25% eosinophils and no signs of allergy as tested by skin prick testing and measurement of total and specific IgE in the nasal secretion). Trigger factors associated by patients with the acute onset of nasal symptoms were none or unknown (42%), weather changes (31%), odors (15%), and noxious or irritating substances (12%). The same sort of patient group with perennial symptoms of nasal hyperreactivity involving sneezing, rhinorrhea, nasal obstruction, pruritus, and frequent hyposmia was later described by others.17 Moneret-Vautrin et al. suggested that NARES is a precursor of aspirin sensitivity.17 Other groups were not able to find eosinophilia in their populations of patients with nonallergic rhinitis.18 The differences between these findings may be explained by group selection.
Note
NARES describes a subgroup of patients with perennial symptoms of nasal hyperreactivity involving sneezing, rhinorrhea, nasal obstruction, pruritus, negative allergy testing, and nasal smear eosinophilia.
The definition of NARES as a subgroup of nonallergic, noninfectious rhinitis is relevant for therapy because patients seem to respond well to nasal corticosteroids.19 This is in contrast to some other subgroups of patients with nonallergic, noninfectious rhinitis.18,20
Atrophic Rhinitis
Primary atrophic rhinitis is characterized by a progressive atrophy of the nasal mucosa and underlying bone, rendering the nasal cavity widely patent but full of copious, foul-smelling crusts. It has been attributed to infection with Klebsiella ozaenae, although its role as a primary pathogen is not determined. Secondary atrophic rhinitis can be associated with chronic granulomatose conditions, radiation, and trauma. In the past it has been reported that excessive surgery leads to secondary atrophic rhinitis; however, recent extensions of endonasal surgery, such as larger skull base tumor removal, medial maxillectomy, and Draf III procedures, show that extensive sinus surgery per se is not a cause of secondary atrophic rhinitis. Some patients develop postsurgical disease comparable to secondary atrophic rhinitis, but the reasons why this happens in a subpopulation of patients who had surgery is not clear, and there does not seem to be a relation to the extent of the surgery.
Smoking Rhinitis
Smoke, in particular cigarette smoke, is known for its irritative effect on mucosa of the respiratory tract. In smoking adults as well as in nonallergic children exposed to passive smoking, a mucosal cellular infiltration with Th2-like profile, including eosinophils, increased IgE+ cells, and increased interleukin 4 (IL-4) is found. Because smoking results in the same clinical picture of rhinitis with rhinorrhea and nasal obstruction, it has to be viewed as a cause of rhinitis in its own right. It may even be that part of the NARES type of nonallergic rhinitis is caused by (passive) smoking or other proinflammatory stimuli inducing an allergy-like inflammatory response.21,22
Gustatory Rhinitis
Gustatory rhinitis is a syndrome of food-induced nasal hypersecretion, characterized by the acute onset of copious watery or, occasionally, mucoid rhinorrhea, occurring immediately after the ingestion of certain foods (often, hot and spicy). Characteristically, excessive rhinorrhea occurs exclusively during food ingestion and begins within a few minutes of eating the involved food, usually with no associated sneezing, pruritus, congestion, or facial pain. Gustatory rhinitis is classified in four subcategories: idiopathic, posttraumatic, postsurgical, and gustatory rhinor-rhea associated with cranial nerve neuropathy. Idiopathic gustatory rhinitis is always bilateral, whereas the other types may be unilateral or bilateral.23
Idiopathic Rhinitis
If we exclude all of the possible causes given above, a significant proportion of the nonallergic, noninfectious rhinitis patient group persists. Syndromes of chronic rhinitis with an unknown etiology were formerly referred to as nonallergic-nonifectious perennial rhinitis (NANIPER). Other terms, such as noninfectious, nonallergic rhinitis, are also purely descriptive.
In accordance with the Allergic Rhinitis and Its Impact on Asthma (ARIA) guidelines, we will be using the term idiopathic rhinitis to describe patients suffering from nonallergic noninfectious rhinitis not classified otherwise (see above).1 Idiopathic rhinitis, formerly called vasomotor rhinitis, is a diagnosis of exclusion and is given to patients who suffer from perennial nasal congestion, rhinorrhea, and/or sneezing with no identifiable etiology. It is unrelated to allergy, infection, structural lesions, polyposis, and other systemic diseases (as mentioned above).
Mixed Rhinitis
Some patients with allergic rhinitis, especially those sensitized to pollen, have symptoms outside the pollen season. These patients have a mixed allergic and nonallergic rhinitis. Also, recently nonallergic rhinitis in some patients was found to develop into allergic rhinitis over a period of 3 to 6 years.24
Chronic Rhinosinusitis with or without Nasal Polyps
The mucosa of the nose and sinus are contiguous; thus, chronic nasal complaints can be induced by (accompanying) chronic rhinosinusitis (CRS). When in doubt of CRS, one should not hesitate to schedule a computed tomography (CT) scan. However, we feel that if the patient history and nasal endoscopy lack criteria pointing to possible sinus problems, such as facial pain, loss of the sense of smell, and disease in the middle meatus, a CT scan is not obligatory for diagnosing idiopathic rhinitis. Also, abnormalities found on CT scans are often seen in normal controls and should be evaluated with care. For an extensive discussion on CRS with or without nasal polyps, see Chapter 16.
Epidemiology
Nonallergic rhinitis is common and is estimated to affect more than 200 million people worldwide. However, its exact prevalence is unknown, and its phenotypes need to be evaluated using appropriate methods for diagnosis and management. It is important to differentiate between infectious rhinitis, allergic rhinitis, nonallergic rhinitis, and CRS, as management differs for each of these. Studies such as the European Community Respiratory Health Survey (ECRHS) and the Epidemiologic Study on the Genetics and Environment of Asthma (EGEA) include patients with allergic and nonallergic rhinitis. The prevalence of allergic and nonallergic rhinitis is reported to be between 10 and 50% of the population. Of these patients, about one-quarter to one-half of cases is reported to be nonallergic.25
Nonallergic rhinitis tends to be adult onset, with the typical age of presentation between 30 and 60 years. Once symptoms begin, they frequently last a lifetime and as described above sometimes evolve into other diseases, such as allergic rhinitis and CRS. If nonallergic rhinitis is present in the pediatric population, it is more likely to be anatomical in nature and to be caused by either adenoid or turbinate hypertrophy, leading to persistent nasal obstruction. In adults, most studies report a clear female predominance, with estimates ranging from 58 to 71% of those affected being female. In a Danish study classifying a population of both adults and adolescents, female predominance held true, with approximately double the prevalence of nonallergic rhinitis in women.
Note
Nonallergic rhinitis is uncommon in children; allergic rhinitis or anatomical factors are much more often the source of rhinitic symptoms.
Considerations on Possible Pathophysiologic Mechanisms
Despite trying to form a nonallergic rhinitis patient group as homogeneous and uniform as possible, it still has to be anticipated that nonallergic rhinitis is a group of different pathophysiologic entities. With the limited data available at the moment, we will speculate which pathophysiologic mechanisms may play a role in nonallergic rhinitis. Whether the roles of these mechanisms are major or minor and which are important for many or a few patients with nonallergic rhinitis have to be further elucidated.
Chronic Inflammatory Disorder
The proposed pathophysiologic mechanisms for nonallergic rhinitis include a chronic inflammatory disorder of antigenic (local allergy) or neurogenic nature.26,27 A pivotal characteristic in the pathophysiologic concept of inflammation is an influx of inflammatory cells in the affected tissue. In symptomatic allergic rhinitis patients, an increase of inflammatory cells has been observed in the nasal mucosa; this increase is positively correlated to nasal complaints. In patients with idiopathic rhinitis, no differences could be found in inflammatory cells in nasal biopsies compared with controls. Also, there was no relation between the number of immunocompetent cells and nasal complaints in patients with nonallergic rhinitis.18,27 A significant reduction of immunocompetent cells in the nasal mucosa of patients with nonallergic rhinitis treated with nasal steroids (fluticasone aqueous nasal spray) was not accompanied by a reduction in nasal complaints;18 inversely, a significant reduction in nasal complaints in a group of patients with nonallergic/idiopathic rhinitis treated with topical capsaicin aqueous nasal spray was not accompanied by a change in inflammatory mediators or a reduction in the numbers of inflammatory cells.28 In a large study with local corticosteroids in 699 patients with nonallergic rhinitis triggered by weather/temperature changes in the United States, no effect of corticosteroids was seen.
Nasal Entopy (Local Allergy)
There is considerable evidence now that a subgroup of patients who were formally considered to be nonallergic actually have a local IgE immune response without any systemic release of IgE26,27 (e.g., negative skin tests and serum-specific IgE). Evidence for this entity is supported by clinical symptoms; local production of allergenspecific IgE (sIgE); a type 2 helper T cell inflammatory pattern in nasal secretions during natural exposure to aeroallergens and a positive response to nasal allergen provocation with local nasal production of sIgE to aeroallergens, tryptase, and eosinophil cationic protein (ECP).
Given the conflicting data from the studies described above, we feel that we need larger studies, preferably conducted in different parts of the world, to further differentiate these subgroups of patients with nonallergic rhinitis and get some impression about the prevalence of these different subgroups.
Neurogenic Mechanisms
The neural regulation of the upper airway is complex and consists of several interacting nervous systems. Sensory, parasympathetic, and sympathetic nerves regulate epithelial, vascular, and glandular processes in the nasal mucosa. The anatomically defined sensory, parasympathetic, and sympathetic neural systems contain heterogeneous populations of nerve fibers, often with unique combinations of neurotransmitters and neuropeptides.29
Parasympathetic/Sympathetic Neural Imbalance
In 1959, Malcomson stated that nonallergic rhinitis was caused by an autonomic imbalance. Normally, base line sympathetic tone provides a constant α-and β-adrenergic receptor stimulation. The marked α1 predominance in nasal blood vessels leads to vasoconstriction. Underactivity of the sympathetic nervous system leads to nasal obstruction. Parasympathetic effects on blood vessels are minimal under basal conditions. Stimulation of cholinergic nerves leads to hypersecretion and dilation of mainly resistance vessels (increase in nasal blood flow) and to some extent capacitance vessels (decrease in nasal patency). Overactivity of the parasympathetic system leads to rhinorrhea.
Some data suggesting a sympathetic involvement in nonallergic rhinitis has recently been published by the Liverpool group. Although the magnitude between patients with nonallergic rhinitis and controls was small, patients with nonallergic rhinitis were found to have an abnormal nasal response compared with controls after isometric exercise and after axillary pressure.30 The specificity of these findings compared with other forms of rhinitis, however, has to be confirmed.
Nonadrenergic, Noncholinergic or Peptidergic Neural System
Researchers in the 1970s and 1980s discovered that perivascular and intraepithelial nonadrenergic noncholinergic (NANC) sensory nerve fibers contain neuropeptides, including vasoactive intestinal polypeptide [VIP], substance P, and calcitonin gene-related peptide (CGRP), which were also demonstrated in the nasal mucosa of various mammals, including humans. The actions of these neuropeptides are limited by degradation by neutral endopeptidase. These neuropeptides are locally released from peptidergic neurons (antidromic release), mainly unmyelinated sensory C fibers, in the nasal mucosa after activation by unspecific stimuli and can be responsible for the symptoms of idiopathic rhinitis.31,32 Stimulation can be induced by inflammatory mediators, such as histamine and bradykinin, but also by several inhaled irritants, such as nicotine, cigarette smoke, formaldehyde, and capsaicin.
The unmyelinated sensory C fibers, or pain receptors, are specifically sensitive to capsaicin (8-methyl-N-vanillyl-6-nonenamide), the pungent agent of hot red pepper. The capsaicin receptor (TRPV1, VR1) is a nociceptive transducer, and the TRPV1 receptor can be found on sensory C fibers in human nasal mucosa ( Fig. 13.1 ). It is activated by a variety of physical and chemical stimuli, including capsaicin. In the nose, the local TRPV1-expressing sensory C fibers play a critical role in the development of nasal hyperresponsiveness to environmental provocateurs. It has been proposed that blocking the nasal sensory nerve stimulation may control nasal hyperresponsiveness and therefore prevent the induction of rhinitis symptoms.
Note
Nociceptive receptors sensitive to capsaicin, the pungent agent of hot red pepper, play an important role in the development of nasal hyperresponsiveness, a fact with significant therapeutic implications.
Nasal capsaicin provocation results in rhinorrhea, nasal blockage, and sneezing. This sensorineural stimulation may produce these effects either through an orthodromic, central neural reflex, associated with efferent parasympathetic neurotransmission, or via antidromic release of neuropeptides from sensory neurons ( Fig. 13.2 ).33 Repeated applications of capsaicin, however, lead to desensitization and even degeneration of peptidergic unmyelinated sensory C fibers. Therefore, the hypothesis, suggested by Wolf,34 among others, that a hyperactive NANC peptidergic neural system is the underlying pathophysiology in idiopathic rhinitis may offer an explanation for the beneficial effect of capsaicin with these patients.
This hypothesis was corroborated by Lacroix, who reported an increased concentration of neuropeptides in a group of patients with chronic idiopathic rhinitis, along with improvement of symptoms by local treatment of capsaicin, resulting in a 50% reduction in CGRP-Li (CGRP-like immunoreactivity) content in nasal biopsies, and a correlation between symptom intensity and CGRP-Li concentration in nasal mucosa. Several double-blind, placebo-controlled studies have shown a therapeutic effect in patients with idiopathic rhinitis with repeated topical applications of capsaicin.28,35,36
The mechanism explaining this therapeutic effect for the most part remains unclear. Despite the CGRPLi reduction found by Lacroix, we did not find any significant difference in panneurogenic staining of nasal mucosa using neurofilament and synaptophysin between capsaicin- and placebo-treated patients 2 weeks, 3 months, and 9 months after therapy, although there was a significant therapeutic effect measured with the visual analogue scale (VAS).28 Also, Wolf et al were unable to show a reduction of NANC fibers in the nasal mucosa in patients with idiopathic rhinitis after successful capsaicin treatment.37 They suggested capsaicin receptor blockage as a possible explanation for the capsaicin treatment effect.
These findings, however, do not discard the hypothesis of a hyperactive NANC peptidergic system, as the activity of this system was not measured. A functional hyperactivity of this system, not captured by histologic changes, could still be the underlying pathophysiologic process in idiopathic rhinitis.
Keh et al specifically looked into nasal hypersensitivity in patients with nonallergic rhinitis by studying the volume-gated sodium channel (VGSC).38 VGSC is the founding member of the ion channel superfamily and is involved in initiation and propagation of action potentials in excitable cells. Neuronal excitability is dependent on sodium channel trafficking, density, and distribution, as well as intrinsic properties of activation threshold and repriming characteristics. Sensory neurons, including nociceptors, are known to express Nav1.7, Nav1.8, and Nav1.9, which are subunits of VGSC. These were found to be significantly increased in the nasal mucosa of patients with nonallergic rhinitis who also had normal levels of inflammatory cell markers compared with those with allergic rhinitis. This indicates that a hyperexcitability (or hyperreactivity) state exists in nonallergic rhinitis, and it was suggested that selective blockers of these sodium channels, administered topically, may have therapeutic potential.38
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