Rhinitis is one of the most common chronic conditions for which medical care is sought.

Studies in the United States and United Kingdom have estimated the prevalence of allergic rhinitis to be between 24-28%. In the U.S., the management of rhinitis accounts for nearly 3 percent of all physician visits with a direct cost estimated at 4.5 billion dollars annually. Though rhinitis alone is never life threatening, its impact on quality of life and both work and school productivity is significant. Furthermore, rhinitis can worsen other chronic conditions such as sinusitis, otitis and asthma, all of which have significant morbidity. The differential diagnosis of rhinitis is summarized on Table 1 Background The nose and nasal cavities have a number of important functions. Airflow into the nasal passages is necessary for both the senses of smell and taste. The nasal passages also act as a filter protecting the lungs from particulate matter. Furthermore, the relatively large surface area of the mucosa covered turbinates act to warm and humidify air prior to entry into the lungs. When airflow is significantly inhibited, all of these functions can be adversely affected. In rhinitis, a combination of nasal mucosal inflammation and increased mucus production can lead to such airflow obstruction. Though rhinitis is commonly thought of as a response to the deposition of allergens on the nasal mucosa, a significant percentage of patients suffering with rhinitis are not allergic. So-called non-allergic rhinitis is not one uniform syndrome but instead a collection of disorders that lead to the classic symptoms of rhinitis including rhinorrhea and/or nasal congestion. The types of nonallergic rhinitis are varied and include vasomotor, hormonal, drug-induced, irritant-induced and many others (Table 2). Non-allergic rhinitis may effect as many as 30-50% of rhinitic patients and is especially common in patients with adult-onset nasal symptoms. Allergic rhinitis typically presents at a younger age and symptoms are usually evident by young adulthood. Symptoms can be purely seasonal or year round (persistent) depending on the sensitizing allergen or allergens. Classically, the symptoms of allergic rhinitis include congestion and/or rhinorrhea accompanied by nasal itch and sneezing. Allergic rhinitis is frequently accompanied by allergic conjunctivitis with symptoms of conjunctival injection, itch, and excessive tearing and crusting. These patients are also more likely to have asthma and atopic eczema, the other diseases of the atopic diathesis. The effect of rhinitis on quality of life is not minimal. Standardized quality of life measures have found that 62% of patients with allergic rhinitis are bothered a great deal while symptomatic. Studies have also shown that almost 80% of patients with allergic rhinitis report difficulty sleeping and thus increased daytime fatigue. In the U.S., allergic rhinitis contributes to approximately 2 million missed school days and 100 million missed work days annually. Furthermore, both adults and school-aged children with rhinitis have been found to have decreased levels of cognitive functioning. Both allergic and non-allergic rhinitis can be associated with secondary complications and comorbidities. The nasal inflammation caused by rhinitis can contribute to the development of both acute and chronic sinusitis. Sinusitis is the third leading disease for which antibiotics are

prescribed in the outpatient setting. Rhinosinusitis has also been shown to contribute to asthma exacerbations and make asthma more difficult to control. Rhinitic mucosal inflammation can also lead to eustachian tube dysfunction and chronic otitis media and/or serous otitis. These disorders in turn can lead to speech delay in pediatric populations and in rare cases permanent hearing damage. Also in children, rhinitis can contribute to craniofacial abnormalities and chronic mouth breathing. Pathophysiology
Allergic Rhinitis

Rhinitis can be induced by allergic stimuli, non-allergic triggers or both (mixed rhinitis) (Figure 1). The underlying mechanism leading to nasal symptoms thus varies depending on the type of rhinitis. Allergic rhinitis only occurs in patients with a genetic predisposition to developing allergies. Though all people are constantly exposed to environmental allergens, it is only those patients with the innate ability to become sensitized that develop symptoms. In these sensitive individuals, repeated exposure to aeroallergens cause B cell activation and maturation into plasma cells, which produce specific IgE antibodies. The IgE binds to specific receptors on the surface of basophils and mast cells. When cell bound specific IgE is cross-linked by the sensitizing allergen, the cells release or generate chemical mediators which cause the allergic symptoms. Activated mast cells release preformed histamine and generate newly synthesized leukotrienes, prostaglandins, kinins, and other compounds. The end result of this mediator release is an immediate hypersensitivity reaction with itching, sneezing, and congestion due to increased vascular permeability, vasodilatation, and increased mucus production. The vascular leakage of plasma proteins contributes to both rhinorrhea and nasal congestion. Further release of inflammatory mediators causes a late-phase reaction that prolongs nasal symptoms after an allergen exposure. Cytokines and chemokines released and generated during this late phase reaction recruit additional inflammatory cells. These cells in turn release further inflammatory mediators which can worsen nasal symptoms and prime the nasal mucosa so that future allergen exposures lead to more rapid onset and often more severe symptoms.
Non-allergic Rhinitis

The underlying mechanisms leading to non-allergic rhinitis are quite variable and less well understood. Vasomotor rhinitis is a non-immunologic syndrome of nasal mucosal vascular engorgement with or without evidence of vascular leak. Nasal symptoms are triggered by a wide range of non-allergens including environmental irritants such as smells and particulate materials, as well as changes in weather and barometric pressure. Chronic sinusitis also causes a variety of nasal symptoms, which must be distinguished from rhinitis in order to treat sinusitis appropriately. Most symptoms of rhinitis involve the anterior aspects of the nose while sinusitis tends to cause posterior symptoms. As the sinus cavities become inflamed, chemical mediators similar to those seen in allergic rhinitis are released leading to rhinitic symptoms. The multitude of other non-allergic rhinitis triggers tend to either cause mucosal vascular engorgement, lead to damage of the nasal mucosa, or act to initiate inflammatory cascades. Diagnosis

Though some rhinitis medications are efficacious in the treatment of both allergic and nonallergic rhinitis, it benefits the patient to have a specific diagnosis. To adequately distinguish between allergic, non-allergic, and mixed rhinitis, a thorough history and physical followed by diagnostic testing is a necessity. Though the end results of nasal congestion and rhinorrhea may not help to distinguish between the disorders, numerous historical clues and subtle differences on physical exam coupled with allergen skin testing or RAST can lead to an accurate diagnosis. Allergic rhinitis usually presents in childhood and there is typically a strong family history of atopic diseases including rhinitis, asthma, and atopic dermatitis. Conversely, 70% of patients with non-allergic rhinitis present after the age of 20 and often there is no evidence of a familial pattern. There is also a strong female predominance in non-allergic rhinitis not seen in allergic rhinitis. Furthermore, patients with non-allergic rhinitis almost always complain of perennial symptoms. Though it is possible for allergic patients to be sensitized to only perennial allergens such as cat or dust mite, most are sensitized to seasonal pollens and thus have seasonal symptoms. While triggers of allergic rhinitis are aeroallergens, the list of non-allergic rhinitis triggers is broad. It includes strong smells and irritants, changes in weather and barometric pressure, hormonal fluctuations, and ingestion of alcohol or food (gustatory). One proviso to the persistent nature of non-allergic rhinitis: many patients are worsened by weather changes seen in the spring and fall and may appear to have seasonal rhinitis. The nature of symptoms also differs between the two disorders. Patients with non-allergic rhinitis typically complain of nasal congestion and rarely have significant pruritus or sneezing. Patients with allergic rhinitis have very significant sneezing and nasal itch. Furthermore, most allergic patients also have troublesome ocular symptoms with conjunctival injection, tearing and itch, while non-allergic rhinitis usually involves only the nose. There are also subtle differences on physical examination. Classically, the nasal mucosa in allergic rhinitis is edematous, boggy and often with a blue-white hue. The nasal examination in non-allergic rhinitis is more variable depending on the underlying cause of the disorder. Nasal mucosa may appear essentially normal with increased clear watery secretions or may be erythematous or even atrophic. Treatment There is significant overlap in the pharmacologic treatment of allergic and non-allergic rhinitis. While the treatment of non-allergic rhinitis is almost solely with medications, successful treatment of allergic rhinitis can also involve allergen avoidance and immunotherapy. Oral antihistamines are often used as first line therapy in patients with rhinitic symptoms. The use of these H1 receptor antagonists had long been limited due to sedating side effects; however the newer second-generation drugs are extremely safe and efficacious with far less sedation. These drugs block the effects of released histamine that is present in high concentrations during allergic reactions. Oral non-sedating antihistamines are most beneficial for the suppression of nasal pruritus, sneezing, rhinorrhea, and accompanying ocular symptoms. These drugs have some, but limited effects on congestion. Because of their lack of decongestant properties, and the fact that histamine is rarely involved in non-allergic rhinitis, oral antihistamines are of little

benefit in treating this disorder. Some older, sedating antihistamines do have drying properties that can have additive benefit in treating rhinorhhea and postnasal drip. The intranasal antihistamine azelastine is not only indicated for allergic rhinitis but also is effective in treating non-allergic rhinitis. In allergic rhinitis, it works similarly to oral antihistamines, blocking the histamine receptor and thus decreasing rhinorrhea, itch, and sneeze. Azelastine is also effective at reducing congestion, probably because topical application places a much higher concentration of antihistamine on the nasal mucosa than is possible with oral antihistamines. In non-allergic rhinitis, azelastine likely acts by both anti-inflammatory activity and neuropetide depletion. Because of the efficacy of topical treatment in rhinitis, there is a move towards using more topical medications such as azelastine and nasal corticosteroids whenever possible, rather than oral systemic medications. Nasal corticosteroids are the mainstay of therapy for both non-allergic and allergic rhinitis. With potent but local anti-inflammatory effects, they are efficacious in treating most rhinitis syndromes regardless of etiology. By decreasing inflammation, nasal corticosteroids decrease mucosal edema and vascular leak improving the symptoms of rhinorrhea and nasal congestion. They also decrease the number of histamine containing mast cells in the nasal mucosa, thus decreasing nasal pruritus and sneezing. Nasal corticosteroids are extremely safe, well tolerated and systemic steroid effects are rare. The most frequent side effects are local irritation and epistaxis, both of which can typically be lessened by utilizing proper spray technique and thus avoiding the nasal septum. Perhaps the greatest difficulty with this class of medication is patient compliance. As it typically takes 1 to 2 weeks of constant use to achieve maximum relief, and nasal corticosteroids frequently are needed chronically, educating the patient of their prophylactic benefits is necessary. Using both nasal corticosteroids and antihistamines (either oral or topical) in combination is almost certain to effectively treat either allergic or non-allergic rhinitis symptoms. Intranasal cromolyn sodium is a mast cell stabilizer indicated for allergic rhinitis. Like nasal corticosteroids, this drug must be used prophylactically and has no beneficial effect on relieving symptoms that are already present. This drug prevents the release of histamine from mast cells and thus primarily prevents sneezing, itch and rhinorrhea. Though it has an unsurpassed safety profile, cromolyn has fallen out of favor because in order to achieve significant benefit it needs to be used 3 to 5 times per day. Antileukotrienes (LTRA) are a relatively new class of medication. These drugs were originally indicated for asthma but have recently been approved in the United States for the treatment of allergic rhinitis. These medications block the effects of leukotrienes, inflammatory mediators produced through the arachadonic acid pathway. Antileukotrienes have been shown to decrease eosinophil counts and nitric oxide production from areas of allergic inflammation. The end result is nasal symptom relief similar to that of non-sedating anti-histamines with modestly decreased rhinorrhea, sneezing, and pruritus. Montelukast, the most commonly used LTRA, is extremely safe in both adults and children. It is well tolerated though not nearly as efficacious as nasal corticosteroids.

Oral decongestants can be beneficial in the treatment of congestion associated with both allergic and non-allergic rhinitis; but can have undesirable side effects. Oral pseudoephedrine hydrochloride used alone or in combination with antihistamines is the most common decongestant. Pseudoephedrine is a sympathomimetic agent that causes vasoconstriction of the superficial blood vessels in the nasal mucosa, as well in other areas of the body. This action decreases swelling of the mucosal tissue and decreases vascular leak improving both rhinorrhea and nasal congestion. Because it is not mediator specific, decongestants can be used in both allergic and non-allergic rhinitis. Unfortunately, tolerance of pseudoephedrine is variable. Side effects include hypertension, nervousness, insomnia, irritability, urinary hesitancy and loss of appetite. It is contraindicated in patients with hypertension. Topical decongestants can provide rapid temporary relief of nasal congestion in allergic and nonallergic rhinitis, however chronic use can lead to complications. They are best used for symptomatic relief of acute severe nasal congestion for very short periods of time. Like oral decongestants, these medications are sympathomimetic and have a similar side effect profile. However, chronic use for even relatively short periods of time (>3-7 days) can lead to rebound nasal congestion. More prolonged use can lead to rhinitis medicamentosa, rebound congestion with gross changes in the nasal mucosa. Both short-acting (phenylephrine hydrochloride) and long-acting (oxymetazoline) preparations are available. Nasal ipratropium bromide is a topical anti-cholinergic spray that may be beneficial in certain patients with allergic and/or non-allergic rhinitis. As cholinergic stimulation can lead to rhinorrhea, this medication can be used to reduce rhiniorrhea in both rhinitis and colds. Ipratropium can be beneficial in patients with difficult to treat rhinorrhea but usually does not help postnasal drip. There are numerous non-pharmacologic measures that deserve consideration when treating rhinitis. Allergen avoidance can both reduce acute exacerbations and lessen the likelihood of a priming effect in patients with allergic rhinitis. Allergen avoidance can only be attempted after skin testing or RAST has identified specific allergens. Immunotherapy has been demonstrated to be extremely beneficial in selected patients with allergic rhinitis. Immunotherapy has no benefit for non-allergic rhinitis patients and thus it is important to distinguish these diseases before considering starting immunotherapy. Though poorly studied, nasal saline lavage has minor decongestant benefits and improves mucociliary function in both patients with allergic and nonallergic rhinitis. In patients where chronic sinusitis contributes to non-allergic rhinitic symptoms, antibiotics may be of benefit. Finally, for many of the underlying conditions contributing to nonallergic rhinitis, it is the treatment of that underlying condition which will be most helpful in alleviating rhinitis symptoms. With so many therapeutic options, a systematic approach to the rhinitic patient is necessary. This begins with a thorough evaluation and accurate diagnosis. The general approach to the management of a patient with allergic rhinitis is to maximize allergen avoidance, minimize the number of medications to insure compliance, and to watch for potential co-morbidities or complications. Skin testing or RAST can not only help direct allergen avoidance, but can also help customize treatment plans so that during patients' high allergen season(s), maximum therapy can be delivered. Almost all patients benefit from nasal corticosteroids. The frequency of

administration (once or twice daily) largely depends on the severity of symptoms. Antihistamines can be added as an as needed medication for breakthrough itching and sneezing, or as a part of the daily regimen. The combination of nasal corticosteroids and azelastine has proved very useful in treating non-allergic rhinitis. Oral decongestants can be considered primarily as an as needed medication in normotensive patients with nasal congestion not adequately controlled by anthistamines and corticosteroids. Antileukotrienes may also have an additive benefit and are most strongly considered in patients with concomitant asthma. Finally, allergen immunotherapy is worth considering in all patients with allergic rhinitis who have symptoms lasting more than 3-4 months per year and for whom medications are used perennially. Immunotherapy when given properly is the only treatment that can potentially affect a cure. To read an in-depth synopsis on Immunotherapy, click here. The general approach to managing non-allergic rhinitis is to treat any underlying conditions that may be contributing to rhinitic symptoms. This may mean finding alternative medications in patients with medication-induced rhinitis, treating underlying sinus disease or hypothyroidism, or asking patients to experiment with different oral contraceptive preparations. If no underlying cause is found, nasal corticosteroids should be considered as first line therapy. Intranasal azelastine is frequently beneficial in non-allergic rhinitis. Like in allergic rhinitis, oral decongestants warrant consideration typically on an as needed basis for breakthrough nasal congestion. Conclusions Allergic and non-allergic rhinitis detrimentally affects the quality of life in a significant portion of the population. The co-morbidities associated with rhinitis can have a further negative impact on patients' wellbeing. Treatment of rhinitis requires that underlying triggers be identified and if at all possible modified. A step-wise approach using pharmacologic and non-pharmacologic therapies can then be implemented, typically with a satisfactory outcome for patients and physicians alike. Figure 1: Relative incidence of allergic rhinitis, non-allergic rhinitis, and mixed rhinitis.

Table 1: Types and underlying triggers of non-allergic rhinitis Vasomotor Pregnancy Chronic Sinusitis Irritant Structural Nasal polyposis Non-allergic rhinitis eosinophilia syndrome (NARES) Atrophic Drug-induced (rhinitis medicamentosa) Hypothyroidism Drug related (aspirin, anti-hypertensives) Ciliary dyskinesia Gustatory Foreign body Cerebral spinal fluid leak Table 2. Differential Diagnosis of Rhinitis Infections Sinusitis Allergic Seasonal Perennial

Non-allergic rhinitis Eosinophilic non-allergic rhinitis (NARES) Vasomotor rhinitis Aspirin intolerance Rhinitis medicamentosa Decongestants Beta blockers Birth control pills Anti-hypertensives Rhinitis secondary to: Pregnancy Hypothyroidism Horner's syndrome Wegener's granulomatosis Anatomical abnormalities causing rhinitis: Foreign body Nasal polyps Nasal septal deviation Enlarged tonsils and adenoids Tumors Cerebral spinal fluid rhinorrhea Atrophic rhinitis