Chronic rhinitis is one of the most common complaints in medical offices worldwide. While it is safe to say that everyone at some point in their lives has experienced symptoms of rhinitis, the true prevalence of chronic nonallergic rhinitis is not known and is difficult to study. The current classification system is in evolution. In its current state, it is imprecise and restricts a patient’s disease process to a single designation. Mixed rhinitis (combined allergic and nonallergic rhinitis) is under recognized. It is more common than either pure allergic rhinitis or nonallergic rhinitis and occurs in approximately 44% to 87% of patients with allergic rhinitis (4,5).

There are also multiple biases in reporting. Firstly, patients with positive allergy testing results are assumed to have only allergic rhinitis, but as mentioned above, rhinitis in an individual patient may have multiple contributing factors. Secondly, patients who present with rhinitis symptoms and respond to a trial of empiric pharmacologic therapy are often presumptively given the default diagnosis of “allergic rhinitis” by their primary care providers without confirmatory testing. This empiric trial of pharmacotherapy is more cost-effective and efficient than allergy testing every patient with rhinitis symptoms but leads to problems when trying to quantify the prevalence of disease. Finally, most prevalence data are collected from physician reporting and retrospective data from the clinical offices of allergists and otorhinolaryngologists where specialty referral patterns may not represent the true prevalence of the general population.

According to extrapolation from population studies, the estimate for patients suffering from either pure nonallergic rhinitis or mixed rhinitis is 45 million persons in the United States (2,4). Twenty-five to thirty-three percent of patients presenting with rhinitis have nonallergic rhinitis (4,5).

The human cost of rhinitis is assessed in terms of symptoms, medication needs, interference with sleep, interference with activities of daily living, work impairment, absences from work and school, impaired learning efficiency, and interference with social activities. Comorbid conditions such as asthma, sleep apnea, sinusitis, and
otitis media contribute to the individual and societal burden of both nonallergic and allergic rhinitis. A recent study by Meltzer et al. compared sleep, productivity, and quality of life in subjects with allergic rhinitis, nonallergic rhinitis, and controls. Self-reported scores on all of these parameters indicate that allergic rhinitis and nonallergic patients perceive their symptoms to adversely impact sleep, quality of daily living, and productivity. Selfreported scores were significantly worse in allergic rhinitis patients (6).

A brief review of relevant nasal physiology is discussed here. This is discussed in more detail in other chapters.

The functions of the nose and paranasal sinuses include filtration, conditioning, and humidification of inspired air; regulation of nasal airway resistance; and sensation of the environment through olfaction and general sensory nerves. A mucosa rich in blood vessels and secretory glands allows the relatively large surface area of the nose to adjust quickly to moment-to-moment changes in the environment. This rapid response can be easily appreciated when the paradoxical nasal vasculature expands with exposure to cold air and quickly produces nasal congestion and rhinorrhea in an attempt to warm and humidify the incoming air. Optimal nasal function depends on a working mucosa and a delicate balance between adrenergic, cholinergic, and sensory inputs. There is a marked α-adrenergic predominance in nasal blood vessels, so vasoconstriction generally prevails.

Norepinephrine and neuropeptide Y are the neurotransmitters responsible for regulation of sympathetic tone, which produces a vasoconstricted decongested state. The sympathetic nervous system has less control over the production of mucus than the parasympathetic system. The parasympathetic autonomic nervous system is largely responsible for rhinorrhea and congestion. Acetylcholine, vasoactive intestinal peptide, neuropeptide Y, nitric oxide, enkephalin, and somatostatin are the primary parasympathetic neurotransmitters. Sensory nerves from trigeminal nerve branches V₁ and V₂ can also regulate blood vessels in response to chemical and mechanical injury. Mucosal injury, inhalation of irritants, mast cell degranulation, substance P, and neurokinin A all cause nasal secretion and dilation of blood vessels. Nociceptive input also initiates systemic reflexes, such as the sneeze, and other autonomic reflexes.

The nose also performs the work of a sentry. It samples and traps particles entering the nares using the vibrissae and mucus. Cilia beat these trapped foreign particles at a rate of 3 to 35 mm/min to the natural sinus ostia and the pharynx. The nasal mucosal lining contains secretory IgA, proteins, and enzymes that help protect from infections. Disruption of any of these processes threatens to alter this delicate nasal homeostasis.

The term “nonallergic rhinitis” suffers from being too inclusive. For example, rhinitis of pregnancy and rhinitis symptoms related to Wegener granulomatosis both fall under the umbrella of nonallergic rhinitis but are clearly different disease processes. Only recently have we begun a concerted effort toward better classification and separation of these diseases through consensus definitions, deeper understanding of the pathophysiology of these diseases, and subcategorization by both pathophysiology and phenotype.

Classification of an individual patient’s disease process is further complicated by the fact that many patients likely suffer from multiple underlying causes of rhinitis simultaneously. The prevalence of mixed rhinitis is likely underappreciated (2). Furthermore, there are, as of yet, no reliable biomarkers of disease or confirmatory tests like skin prick testing for allergic rhinitis. Differentiating between subcategories of nonallergic rhinitis, after allergic causes have been ruled out, relies largely on good history taking and exclusion of other potential diagnoses.

This chapter reviews the major subcategories of nonallergic rhinitis according to contemporary classification schemes and terminology.

IR is a diagnosis of exclusion but comprises roughly 60% of nonallergic rhinitis. Over the years, IR has been known by several terms, including noninfectious nonallergic rhinitis, nonallergic noninfective perennial rhinitis, perennial nonallergic rhinitis, intrinsic rhinitis, and vasomotor rhinitis. When allergy, mechanical obstruction, and infections have been excluded as the cause of rhinitis, a patient is given a diagnosis of nonallergic rhinitis. When occupational hazards, environmental irritations, hormonal contributions, nasal eosinophilia, medication effect, age-related changes, and autonomic disturbances have been ruled out, the remaining nonallergic diagnosis is IR. The fact that IR accounts for more than half of the constituency of nonallergic rhinitis reflects our incomplete understanding of the pathophysiology of rhinitis.

By definition, IR does not have a singular demonstrable etiology. Many theories continue to be investigated including: a chronic inflammatory state, an imbalance between sympathetic and parasympathetic input to the nasal mucosa, a nonadrenergic noncholinergic mechanism of stimulating nasal mucosa via peptides such as substance P and vasoactive intestinal peptide acting on sensory fibers, central nervous system sensory dysregulation, and nitric oxide synthase induction in vascular smooth muscle cells causing vasodilation (7). These are worth mentioning as currently outstanding theories. Likely it will be revealed that IR makes up a collection of heterogeneous diseases with equally heterogeneous pathophysiologies.

Patients presenting with IR will complain of refractory nasal congestion and rhinorrhea predominantly. Sneezing and pruritus are less common. Quantifying patient symptoms and impact of disease allow the physician to translate this constellation of symptoms into a treatable disease process.

The workup reviewed here for IR applies to all of the following subcategories of nonallergic rhinitis. The patient presenting with rhinitis symptoms should be asked not only how long the symptoms have been present but more specifically, “For how many hours per day are you affected by these symptoms.” This will help to differentiate what is problematic disease from what may be a normal physiologic nasal reaction. A standardized daily record chart of symptom duration and intensity can be helpful for quantifying disease burden and is often discrepant from the verbal report at the first visit (7) (see Table 30.1). Impact of the symptoms on the individual and his/her daily activity is a crucial piece of information and can be ascertained with the simple question, “Which symptom is most bothersome to you?” Without this information, it is sometimes difficult to focus the treatment plan and measure improvement.

A thorough history should help the physician to rule out other causes of nonallergic rhinitis. Exacerbating and alleviating factors and where these factors occur (e.g., in the workplace) should be ascertained. It is important to clarify the patient’s current and previous nasal regimens including what medications were/are being used, the frequency of use (i.e., compliance), what worked, and the reasons for cessation of the medication. Saline and over-the-counter medications are pertinent. Review of the patient’s entire list of medications is also necessary to look for possible drug-induced rhinitis. Smoking history and other potential irritant exposures in the past 6 months should be sought. If the patient is a woman, recent and current pregnancy status should be asked.

Anterior rhinoscopy and nasal endoscopy should be performed to rule out structural contributions to the patient’s complaints. A computerized tomography (CT) scan of the sinuses can be helpful to evaluate for evidence of chronic sinusitis or nasal masses not seen on exam; however, clinical suspicion should guide the pursuit of imaging studies. A CT scan is not required for the diagnosis of IR. Allergy testing either by skin prick or allergen-specific serum testing is important to rule in or out possible allergic rhinitis. In practice, however, an empiric trial of saline irrigations with either a topical antihistamine or topical steroid nasal spray is typically first initiated for 6 to 8 weeks. If symptoms persist, allergy testing should be pursued.

The cold dry air (CDA) provocation test may provide an additional objective test to differentiate between patients with IR and controls but is currently a research tool not yet in clinical use. Pulmonary CDA provocation of patients with asthma results in bronchial obstruction, and it has been found to be a suitable method for assessing bronchial hyperreactivity (8,9). Histamine and methacholine have been used to test nasal reactivity in allergic rhinitis patients. However, histamine could not differentiate controls and IR patients (10). Methacholine similarly could not differentiate IR patients with congestion as their primary complaint from control subjects (11). Braat et al. (12) demonstrated that IR patients had increased mucus production and nasal blockage in a dose-dependent manner to a standardized CDA challenge. CDA in their study proved less sensitive than histamine but more specific.

A wide variety of both pharmacologic and surgical therapies exist for symptom-directed treatment of IR. Azelastine is FDA approved for the treatment of nonallergic rhinitis. A recent randomized double-blind parallel-group multicenter trial showed efficacy of both available topical antihistamines (e.g., azelastine and olopatadine) for relief of nasal congestion, rhinorrhea, postnasal drip, and sneezing associated with IR (13). Two older placebo-controlled studies lend additional support to the use of intranasal antihistamines as first-line therapy for IR (14,15). Azelastine has been shown to have both antihistamine and anti-inflammatory effects in vitro and in vivo (16), which may explain its effectiveness in the treatment of both seasonal allergic rhinitis and nonallergic rhinitis (17). The most commonly reported side effect is taste disturbance.

Beclomethasone aqueous and fluticasone aqueous are FDA approved for the treatment of nonallergic rhinitis. It is reasonable to trial a topical nasal steroid alone or in conjunction with an intranasal antihistamine for treatment of IR. The combination of a nasal steroid with a topical antihistamine has not yet been shown to have added benefit
in IR though the combination has been shown to be beneficial in the treatment of patients with seasonal allergic rhinitis (18).

Ipratropium bromide aqueous is most effective for the rhinorrhea associated with nonallergic rhinitis and is a good pharmacologic option if this is the patient’s primary complaint. It has also been shown to be effective at improving mood and quality of life scores in nonallergic rhinitis patients but was no better than placebo at relieving congestion, sneezing, or postnasal drip (19). The recommended starting dose is two sprays three to four times daily but once a therapeutic effect has been achieved, this can often be decreased to once or twice daily dosing.

Nasal saline spray or irrigation is often thought as an “active placebo” in clinical trials due to its reported effectiveness for nonallergic rhinitis patients. Saline irrigations have been shown in multiple studies and in a systematic Cochrane review to be well tolerated and beneficial in a majority of patients with rhinosinusitis (20). Daily isotonic nasal irrigations should be a component of the daily nasal regimen for any patient with IR.

Systemic antihistamines are a consideration if sneezing or pruritus is a major symptom, however, this is not as common with IR. Oral decongestants may be an adjunct for decongestion of a severely congested nose when starting topical therapies or for temporary symptom relief of episodic exacerbation of symptoms. Oral decongestant use should be limited in those with a history of hypertension or cardiac disease due to the potential to exacerbate these conditions. Topical decongestants play a very limited role in treatment of IR and patients should always be counseled to avoid these medications for any longer than 3 days at a time.

Capsaicin is a substance found in hot peppers that induces rhinorrhea and congestion when ingesting spicy foods. Nasal capsaicin provocation results in rhinorrhea, nasal blockage, and sneezing via stimulation of the unmyelinated sensory C fibers or pain receptors. Repeated intranasal applications of capsaicin in some individuals, however, lead to desensitization by prolonged stimulation of an ion channel receptor which is sensitive to physical and chemical nociceptive stimuli. This ion channel receptor, called Transient Receptor Potential Vanilloid type 1 or TRPV1, is found on epithelial cells, vascular endothelial cells, submucosal glands, and nerves in human nasal mucosa and is capable of regulating nasal secretion and congestion (21).

One recent randomized double-blind placebo-controlled trial demonstrates that capsaicin is effective for relief of symptoms in patients with IR without significant side effects or rebound (22). This supports the findings of several previous randomized trials (23,24). The onset of the relief occurred within 60 seconds and was present for at least 9 months without change in cellular mediators or neural tissue density (22,24). Capsaicin has not reliably shown this same benefit in allergic rhinitis patients (25,26).

Capsaicin spray is currently available under the brand name Sinus Buster in the United States. There is no current consensus regarding the dose and frequency of administration but all recent studies have demonstrated that less than 2 weeks of treatment is adequate for relief and can be repeated when symptoms recur (22,23,24). In one study, one spray given every 2 to 3 days over 2 weeks was found to be as efficacious as a single day treatment during which one spray was given each hour for 5 hours (24). From its initial studies, capsaicin seems to be an appealing potential option for treatment of IR. It has a quick onset of action, a short course of treatment, and aside from a slight burning sensation upon administration, has minimal reported side effects. However, larger clinical trials are needed before formal recommendations can be made regarding its safety and use intranasally. Caution should be used in patients with concomitant lung disease. Inhaled capsaicin is a welldocumented stimulator of the cough reflex and severe, fatal asthma attacks have been reported with inhalation of capsaicin when used as an incapacitating agent (i.e., pepper spray) in asthmatics (27).

Surgical options for refractory symptoms of rhinitis include various methods of inferior turbinate reduction and vidian neurectomy. A myriad of approaches to turbinate reduction have been described including steroid injection, electrocautery, cryotherapy, coblation, laser reduction, microdebrider-assisted partial turbinectomy, complete inferior turbinectomy, and simple out-fracture (28). In general methods that are destructive or disruptive to mucociliary function such as complete turbinectomy and electrocautery should be avoided. Submucosal methods prevail over extramucosal approaches (29). Steroid injection into the turbinate can be temporarily effective but topical decongestion for 5 minutes prior to a slow steady injection is paramount as there are remote case reports of blindness after steroid injection. From a recent review of techniques, microdebrider-assisted partial turbinoplasty and holmium-YAG laser turbinate reduction demonstrated the most durable improvement in nasal patency lasting for at least 3 years (28,30,31,32).

Vidian neurectomy was introduced in the 1960s as a means of reducing severe rhinorrhea related to “vasomotor (autonomic) rhinitis” from presumed overstimulation of the parasympathetic system. This was initially described through a transantral approach to the pterygoid canal. Initial reports demonstrated lasting efficacy (33) but subsequent studies showed recurrence of symptoms in 71% of patients at 1 year postprocedure (34). Over the years, the original transantral approach to vidian neurectomy has evolved into an endoscopic approach that carries less surgical morbidity. A recent study showed long-term effectiveness of endoscopic vidian neurectomy at controlling rhinorrhea and nasal congestion up to 7 years (35).

The aim of the vidian neurectomy is to cut the efferent pathway of the parasympathetic reflex, which causes rhinorrhea from irritation of the nasal mucosa. Dry eye is a
common side effect of the procedure as there are preganglionic parasympathetic fibers from the greater superficial petrosal nerve which pass through the pterygoid canal as part of the vidian nerve to supply to lacrimal gland. However, in a recent study of the endoscopic approach most patients eventually recovered from xerophthalmia within months (35). This may be due to the fact the nerve was addressed with bipolar cautery or laser without removal of a segment of nerve as originally described.

Studies from Japan report a modification of vidian neurectomy that affords the same relief of rhinitis symptoms as vidian neurectomy with theoretically less risk of xerophthalmia (36,37,38). In the posterior nasal neurectomy technique, sensory and autonomic branches are ligated distal to the pterygoid canal just after exiting the sphenopalatine foramen as they travel alongside the sphenopalatine artery. Endoscopic vidian neurectomy and posterior nasal neurectomy are ultimate surgical options for patients with intractable rhinitis refractory to other management strategies.

NARES is a clinical syndrome in which symptoms such as sneezing, pruritus, and profuse watery rhinorrhea seem decidedly allergic, however, there is (a) an absence of demonstrable systemic atopy and (b) marked eosinophilia on nasal smear. Nasal smear must show greater than 20% eosinophils to be diagnostic. Nasal symptoms in patients with NARES are often more severe than in their allergic rhinitis counterparts (39) and anosmia is present more frequently (2).

NARES represents roughly 15% to 33% of adults with nonallergic rhinitis (39,40). There is an association of NARES with aspirin-exacerbated respiratory disease (AERD) and a number of these patients go on to experience aspirin sensitivity and polyposis in the future. Some reports have suggested that NARES is an early manifestation of AERD and the presence of eosinophilia should be interpreted as a marker for future aspirin intolerance and polyps (39).

The pathophysiology of NARES is not yet understood. Eosinophils and activated mast cells seem to play an important role. Eosinophils have been shown to release toxic substances such as major basic protein and eosinophilic cationic protein into the nasal mucosa (41). Physiologic studies on patients with nonallergic rhinitis have shown a correlation between eosinophilia and prolonged mucociliary clearance on saccharin clearance tests (42

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