CHAPTER 46 Nonallergic Rhinitis

• The incidence of chronic rhinitis is high in the United States and poses a large burden on society, school attendance, and work productivity. Nonallergic rhinitis (NAR) can be clinically present in an isolated form or in a combined form with some varying mixture of an allergic component. Concerning NAR, females tend to be afflicted more, and the incidence also increases with age. Despite what is known about NAR, much is also unknown, making the diagnosis process—along with trying to achieve good overall control—difficult, leading to frustrated patients and clinicians.

• Often the symptomatologies of NAR and allergic rhinitis (AR) are quite similar, and careful differentiation is needed. Differentiating the typical symptoms of rhinitis, which include rhinorrhea, congestion, sneezing, change in smell, and postnasal drip, into either an allergic or nonallergic category is difficult. Most often, if the etiology is not clear and results of typical allergic rhinitis testing (skin and radioallergosorbent testing) prove to be negative, then NAR must be considered. However, this is not the endpoint because effort must be taken to classify the subtype of NAR present in order to maximize therapy.

• The pathophysiology of NAR is quite complex, and much is yet to be discovered. Numerous factors play a role in nasal physiology and control, including intricate innervation by sensory, parasympathetic, and sympathetic nerves. Other factors that complicate the understanding are various inflammatory cascades and a multitude of cellular and protein reactions, most of which are not fully understood. Provocation testing has been one of the principal tools utilized in the attempt to assess the pathophysiology of NAR. Histamine, muscarine, cold air, adenosine monophosphate, and capsaicin are among the more commonly studied agents. Research is also evaluating the potential role of immunoglobulin E, mast cells, and other known factors typically thought of in AR that could also play a role in NAR, despite the absence of systemic atopy.

• Determining the numerous different types of NAR can be daunting. The various types of NAR presented and discussed in this chapter are divided into the following categories: NAR with eosinophilia syndrome, hormone-related NAR, medication-induced NAR, irritant-induced NAR, NAR due to chemical exposure, atrophic rhinitis, NAR due to anatomic obstructions, NAR due to systemic disorders, and idiopathic NAR. The rationale for this division is based on therapy and management, in that the treatment of each type of NAR within the specific category has a similar basis. Despite the numerous types, the foundation of NAR is the same: some exposure or alteration in the nasal mucosa, either external to the body or within the body, that alters the normal homeostasis of the nasal mucosa, inducing the resulting NAR symptoms. The diagnostic picture can be complicated by the presence of coexistent AR.

• If after an exhaustive search, no clear etiology is noted, the condition is termed idiopathic or vasomotor rhinitis. This seems to be the most common form of NAR and often the most difficult to treat. Historically, idiopathic rhinitis was thought to be related to excessive parasympathetic or reduced sympathetic activity of the nasal mucosa. This process is likely to be only part of the whole picture of vasomotor rhinitis, because other theories have also been proposed.

• The single most important factor in attaining a proper diagnosis is a complete history. Absolute points that must be covered are detailed symptomatology, potential inciting agents or triggers, past and present medication use, and other systemic disorders. A complete examination for local and/or anatomic factors is also necessary, which should include a nasal endoscopy.

• The best overall treatment tool is avoidance of known inciting agents. Medical therapy should be an adjunct to this step. Medications that have proved to be effective include topical nasal corticosteroids, antihistamines, and anticholinergics. Oral preparations of these agents have limited value and their use minimized compared with direct, topical therapy. Decongestants, either oral or topical, should also be used in a limited way and only in combination with topical therapies.

• Surgical intervention for NAR is usually reserved for those whose symptoms are not controlled with conservative medical therapy. Surgery is also beneficial for those with clear, overwhelming anatomic obstructions. Various surgical procedures described for NAR include septoplasty, inferior turbinate reductions, vidian neurectomy, and other procedures to relieve anatomic obstructions.

Chronic rhinitis presents a tremendous problem for the health care industry; 10% of the population is affected by chronic or recurrent nasal symptoms, with an estimated 17 to 19 million Americans affected by nonallergic rhinitis (NAR).^1,² The prevalence of patients with NAR among otolaryngology and allergy clinic populations ranges from 28% to 60%, and its incidence rises with age.^3,⁴ Of the patients who present to the otolaryngologist’s office, 50% are diagnosed with a form of NAR, and the rest are diagnosed with allergic rhinitis (AR).^1,⁵ In a survey of 975 patients visiting allergists’ offices for chronic rhinitis, the National Classification Task Force found that 43% were diagnosed with pure AR, 23% with NAR, and 34% with mixed AR and NAR. Thus, 57% of patients with chronic rhinitis have some component of NAR.⁶ Women seem to be more affected by rhinitis, with one study noting 70% of women aged 50 to 64 years experiencing some form of rhinitis during a 1-year period.^7,⁸

Problems that result from chronic rhinitis include sinusitis, the development of polyps as a result of chronic inflammation and obstruction, eustachian tube dysfunction, laryngeal dysfunction, chronic otitis media, hearing loss, sleep-disordered breathing, disorders of the sense of smell, malaise, and fatigue. In fact, rhinitis is present in as many as 80% of patients with chronic fatigue syndrome.⁹ These symptoms often interfere with school or work performance, and a lack of productivity is worsened by the need for frequent doctor visits. In a survey of rhinitis patients, one fourth noted restricting their choice of occupation or residence to reduce their symptoms.¹⁰ In addition, medications—although usually helpful—may elicit undesirable side effects, such as drowsiness, epistaxis, palpitations, and nasal dryness, compounding the overall effect of NAR.¹¹

NAR and AR have similar presentations, manifestations, treatments, and effects on school and work performance. Thus, statistics for AR can be used to infer the economic impact of NAR. In many instances, AR and NAR are often indistinguishable and coexist.^1,² Twenty million to 40 million Americans are affected by AR, and the direct costs for doctor visits and medication expenses are at least $1.9 billion annually. The cost of lost productivity approaches $3.8 billion annually.¹²

Despite all of the preceding facts, defining NAR is difficult. Symptom presentation is nonspecific, and patients may present in a variety of ways. Most commonly a patient complains of rhinorrhea, nasal congestion, and sneezing despite having no history of allergies and negative results of skin testing and nasal cytology. Unfortunately, after allergy has been ruled out as the etiology of the rhinitis, these patients may be diagnosed with “vasomotor rhinitis,” a blanket term used to diagnose affected patients.^2,^13,¹⁴ Because no unifying criteria exist for this broad class of problems, further investigation and workup are generally abandoned by most clinicians, especially because there are no clear diagnostic tests. Treatment is indiscriminate, with varied responses seen among patients. The results are often unsatisfactory and frustrating for both the physician and the patient.

Chronic rhinitis has been described in the literature under many terms. Historically, vasomotor rhinitis has been favored, but distinct vascular or motor nerve dysfunction has been difficult to identify.⁴ Other terms used in the literature include perennial rhinitis, idiopathic rhinitis, perennial NAR, and nonallergic, noninfectious perennial rhinitis.^6,^15,¹⁶ Nonallergic rhinitis (NAR) is the term used here to describe the variety of rhinitis-related problems that cause intermittent rhinorrhea, nasal congestion, and nasal obstruction unrelated to allergy. Nasal itching and sneezing with NAR occur to a lesser extent than seen in AR.

Various forms of and contributing factors for chronic NAR are outlined in this chapter; the research into its pathophysiology is also briefly reviewed. This chapter provides the background for the development of a systematic evaluation and treatment plan for patients with NAR.

Pathophysiology

Nasal Function and Innervation

The effects of NAR cannot be fully appreciated without a brief review of nasal function. Nasal function includes temperature regulation, olfaction, filtration, and humidification of inspired air. The nasal lining also produces secretions that contain immunoglobulin (Ig) A, protein, and enzymes to provide lubrication and protection. Secretions trap particulate matter, and then nasal cilia propel the matter toward the natural ostia. The cilia move at a frequency of 10 to 15 beats per minute, and the mucous blanket streams at a rate of 2.5 to 7.5 mL per minute.¹⁷

Innervation of the nasal mucosa is highly organized and very complex. Regulation of mucosal vasculature and glandular secretions is controlled by the autonomic system. The sympathetic nerves form one half of the efferent nasal reflex arc. Once stimulated, sympathetic nerves release norepinephrine and neuropeptide Y, which cause vasoconstriction of the nasal vasculature. The parasympathetic nerves constitute the other half of the efferent nasal reflex arc. After they have been stimulated, parasympathetic nerves release acetylcholine, norepinephrine, and vasoactive intestinal peptide. Cholinergic neuropeptides and neurotransmitters stimulate the serous glands of the nasal mucosa and increase mucus secretion. Unilateral stimulation of the efferent reflex arc leads to a bilateral response.^17,¹⁸

Sensation originates primarily from the trigeminal nerve. Afferent ethmoidal nerves provide sensory innervation to the epithelium, vessels, and glands. C fibers, which are unspecialized afferent sensory nerves that react to pain and to changes in temperature and osmolarity, are the most relevant type of sensory fibers in NAR. They are stimulated by inflammatory mediators such as histamine and bradykinin and are involved in centrally mediated reflexes. Research has also elucidated their stimulation by inhaled irritants like nicotine, smoke, formaldehyde, and capsaicin, which is discussed later. Once stimulated, C fibers depolarize and release neuropeptides such as substance P and calcitonin gene–related peptide, which increase vascular permeability and activate the submucosal glands. The result is the acute stimulation of glandular cells, endothelial cells, and epithelial cells within the nasal mucosa, thereby causing the sensation of itching, rhinorrhea, and/or burning.⁵

A disorder of any component of the nasal mucosa may lead to NAR. The efferent parasympathetic nervous system produces glandular secretions and the sympathetic limb causes nasal decongestion, both of which are normal physiologic activities. However, hyperresponsiveness of the afferent sensory limb causes an exaggerated efferent response to neuronal stimuli; the result is the oversecretion of mucus and increased nasal congestion due to capillary plasma exudation. The same symptoms are seen with normal afferent input and a hyperreactive efferent arc. Less commonly, an intrinsic epithelial problem or central nervous system dysregulation is the source of disordered responsiveness. Unfortunately, given the complex interaction of mucosal regulation, it has been difficult to isolate a source for specific study.¹⁶ The nonspecific and variable symptoms of NAR are confounding; this situation compounds the difficult task of identifying the exact pathophysiologic source. One suggested mechanism in the complex pathophysiology of NAR involves the inflammatory cascade, including prostaglandin and leukotriene products, but there is still equivocal and contradictory evidence as to the importance of these substances.¹⁹

Provocation Testing

Various nasal provocation tests have been used in attempts to characterize NAR and nasal reactivity. The methacholine challenge test is used to study glandular responsiveness; this provocation bypasses sensory nerve stimulation, vascular effects, and, thus, complaints of congestion. It also determines glandular responsiveness independent of allergen or immunologic mediation.^4,¹⁵ Methacholine is a muscarinic cholinergic receptor agonist that stimulates cholinergic receptors in the submucosal glands. Intranasal administration leads to a dose-related increase in glandular secretions and rhinorrhea. Patients with NAR have higher glandular activity than controls.¹⁶ However, this hyperresponsive reaction is not unique to patients with NAR. Patients with AR respond to methacholine in a similar fashion^4,¹⁶; therefore, methacholine can be used to differentiate patients with AR as well as patients with NAR from controls but not to differentiate these patient groups from each other.

Histamine placed in the nose stimulates symptoms of rhinitis and is widely used to study both AR and NAR.^4,^5,^20,²¹ Histamine provocation increases vascular permeability, thus causing sneezing, pruritus, rhinorrhea, and nasal obstruction.^4,¹⁶ Patients with NAR have a higher response than controls.²¹ The response experienced by patients with NAR is less than that seen in patients with AR, but there is significant overlap in the responsiveness of these two patient populations. Definitive indications of histamine as an influence in the physiologic mechanism of NAR are lacking.^5,¹⁶ However, these results suggest that vascular hyperreactivity may be a contributing factor in NAR.

The effects of cold, dry air on nasal mucosa have been extrapolated from asthma research.^22,²³ The studies demonstrate that nasal inhalation of cold, dry air causes drying of the nasal mucosa; this drying induces symptoms of rhinorrhea, congestion, and occasional sneezing in susceptible patients. Cold, dry air increases the tonicity and osmolality of nasal secretions, causing release of inflammatory mediators, afferent stimulation, activation of the parasympathetic reflex arc, increased epithelial shedding, production of mucus, and symptoms of rhinitis. One of the current thoughts regarding the physiology of cold air rhinitis is that the cold, dry air causes sensorineural stimulation, which leads to hyperosmolarity; these changes, in turn, lead to mast cell activation. However, there is also evidence supporting a variation of this theory, which suggests that the cold air induces nasal mucosa water loss with resulting hyperosmolarity. This effect would then stimulate sensory nerves, activate mast cells, and damage nasal epithelium. The role of mucosal mast cells is to release mediators that increase fluid movement, decrease hyperosmolality, and reestablish homeostasis by altering nasal vasculature, epithelium, and glandular cells.^23,²⁴ Regardless of the specific mechanism, the general hypothesis of cold air–induced rhinitis is the inability of the mucosa to compensate for the high water loss that results from this specific environmental exposure.²⁵ Togias and associates²⁶ proposed that studying such mast cell mediator release with resultant inflammation and increased vascular permeability through either immunologic or physical stimuli provides models for the study of multiple forms of rhinitis.

Stjarne and colleagues ²⁷ have looked at capsaicin as it relates to nasal mucosal provocation. Placement of capsaicin on the nasal mucosa leads to sensory nerve stimulation, with specific stimulation of the C fibers. The result is cholinergic parasympathetic reflex activation, which causes rhinorrhea, congestion, sneezing, and nasal burning.^27,²⁸ The symptoms occur independent of histamine release or mast cell activation, suggesting that these results are selective for patients with NAR.²⁷

In 1991, Stjarne and colleagues ²⁷ published studies of nasal mucosal desensitization with capsaicin, the results of which have been reproduced by other groups.^29,³⁰ Local treatment of the inferior turbinate with capsaicin for 3 consecutive days led to sensory nerve release, neuropeptide depletion, and disrupted function of capsaicin-sensitive nerve endings. Subjects reported a more than 50% reduction of complaints of nasal blockage and discharge when challenged with a dose of capsaicin at 1-month follow-up. These results correlated with an improved appearance of the mucosa and were maintained at 3-month follow-up; symptoms and mucosal appearance reverted to pretreatment levels by 6 months. A selective effect on patients with NAR was again suggested.²⁷

The preceding tests represent examples of ways to study the pathophysiology of NAR, but no test has been found to be a specific model for the study of this disorder. For each of the provocation tests, there are studies that support the contrary argument; also, various methods are used in these studies to assess the responsiveness, further clouding the results. It has been difficult to find a response that definitively distinguishes between patients with NAR and those with AR.^4,¹⁶

Allergic Component

Later research has evaluated the role of mucosal IgE production with and without provocation testing in patients diagnosed with NAR. IgE production within nasal mucosa in conventional AR has been studied extensively. Rondon and colleagues ³¹ reported that a subgroup of NAR patients also produce local IgE upon nasal provocation testing. This response has also been studied and demonstrated in a clinical study by Wedbäck and associates.³² These results suggest there may be a subgroup of NAR patients who have an allergic disease pathway while still exhibiting negative systemic atopy; this group could possibly be those with NAR with eosinophilia (NARES).³³

Classification

Nonallergic Rhinitis with Eosinophilia

A classification scheme for the major forms of NAR is listed in Box 46-1. Jacobs and colleagues³⁴ first described NARES in 1981, separating it from traditional NAR. The complex consists of perennial symptoms with episodes of watery rhinorrhea, pruritus, epiphora, and sneezing in patients with negative or irrelevant reactions to common allergens on skin or in vitro testing. The majority of patients deny having specific triggers, although some complain that weather changes or exposure to irritant chemicals is troublesome. Cytologic examination of nasal secretions from such patients shows marked eosinophilia. This reaction may occur as part of a continuum of chronic sinusitis, nasal polyps, and Samter’s triad or as an isolated disorder in up to one third of patients presenting with NAR.^1,^5,^35,³⁶ Unfortunately the exact pathophysiology of this condition is not clear. However, as noted previously, studies have shown that numbers of mast cells, IgE-positive cells, and eosinophils are increased in the nasal mucosa of patients with AR and NAR, possibly as a consequence of localized IgE-mediated reactions. In addition, nasal neural dysfunction has also been described to contribute to the symptomatology in patients with NARES.^33,^37,³⁸

Box 46-1 Classes of Nonallergic Rhinitis

Nonallergic rhinitis with eosinophilia

Hormone-related disorders:

Postmenopausal status

Medications (see Box 46-2) (rhinitis medicamentosa)

External beam radiation treatment

Associated systemic disorders

Idiopathic

Emotional

Exercise-induced

Hormonal

Through direct effects on the nasal mucosa, hormones may cause mucous gland hyperreactivity and increased rhinorrhea.¹ Hypothyroidism and acromegaly are metabolic conditions that result from hormone imbalances and that are associated with nasal symptoms and rhinitis.⁵ Fluctuating serum hormone levels during menstruation can lead to nasal symptoms in women of childbearing age. Similarly, rhinitis may arise as a result of changing blood hormone concentrations during puberty.^3,⁵

Rhinitis during pregnancy is a well-known entity, affecting 22% of pregnant women. This proportion increases by 69% in women who also smoke.³⁹ The prevalent nasal symptoms are rhinorrhea and congestion, and a review of the patient’s history frequently elicits prior problems with rhinitis. During pregnancy, vascular changes and physiologic expansion of circulating blood volume may contribute to increased nasal vascular pooling and progesterone-induced vascular smooth muscle relaxation.^1,⁴⁰ The severity of rhinitis during pregnancy has been shown to parallel blood estrogen levels.⁵ Direct nasal effects from changes in levels of estrogen, progesterone, prolactin, and placental growth hormone are thus possible causes of the development of this condition. However, no current theory regarding the etiology is convincing, and a multifactorial etiology seems most plausible.^40,⁴¹

Medication-Induced

Rhinitis is a common side effect of a myriad of medications; a list of such medications is shown in Box 46-2. Aspirin and nonsteroidal anti-inflammatory medications are well known for their association with airway reactions, including sinusitis and asthma. Nasal symptoms and congestion are associated with several psychotropic agents (e.g., thioridazine, amitriptyline, perphenazine) and antihypertensives (e.g., β-blockers, α-blockers, angiotensin-converting enzyme inhibitors, vasodilators). Hormonal replacement and oral contraceptives can also lead to NAR.^5,⁴² Asking a patient with rhinitis about medication overuse and abuse is critical; rhinitis medicamentosa is a unique entity that results in rebound congestion after persistent use of topical nasal decongestants or cocaine.

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Nonallergic Rhinitis