Nonallergic Rhinitis

Localized Inflammation

The role of inflammation in NAR is controversial. Certain patients with NAR are believed to demonstrate entopy, or a localized nasal allergic and inflammatory response without systemic evidence of atopy. These patients have been shown to have normal serum IgE titers, yet positive nasal provocation testing upon exposure to dust mites; nasal lavage fluid in these NAR patients has also been shown to have higher than average levels of dust mite–specific IgE. Histologic studies of the nasal mucosa in NAR have shown a pattern of inflammation similar to that seen in AR patients, with increased mast cells and eosinophils compared to control patients. There is also a higher level of total (CD3 ⁺ ), activated (CD25 ⁺ ), and allergen-naïve T lymphocytes (CD45RA ⁺ ) compared to healthy controls. One study found that the presence of inflammation was correlated with worse disease burden.

However, not all studies support the entopy and proinflammatory theory in IR. For example, nasal biopsy evaluation in certain vasomotor rhinitis (VMR) patients found no increase in inflammatory cells. These contradicting results may be in part due to patient selection and variances in tissue sampling techniques, but also could be attributable to disparate pathophysiologies that underlie the varying subtypes of NAR. More research is required to further explore the role of inflammation in NAR.

Nociceptive Dysfunction

In a subset of patients with idiopathic NAR, there is no evidence of inflammation and the nasal mucosa is similar to that of normal control subjects. The lack of inflammation leads some to suggest that this subtype of NAR should not be classified as a “rhinitis” but rather as a “rhinopathy.” These same patients have hyper-responsive nasal mucosa, particularly when exposed to cold dry air (CDA). These NAR patients experience a dose-dependent nasal obstruction in response to cold air that is not seen in AR or control patients. In this population, it is hypothesized that there is a hyperreactivity of the nasal afferent sensory nerves that originate primarily from the trigeminal nerve, which contain unmyelinated nociceptive C fibers.

These sensory C fibers in the nasal mucosa react to pain, changes in temperature, and environmental irritants by releasing neuropeptides, including substance P, calcitonin gene-related peptide, and neurokinins A and B. Release of these neuropeptides, mediated through activation of transient receptor potential cation channel subfamily V receptor 1 (TRPV1), increases vascular permeability and submucosal glandular secretion, resulting in the clinical symptoms of nasal congestion and rhinorrhea. Patients with IR have higher TRPV1 expression in the nasal mucosa and higher concentrations of substance P.

Capsaicin, which acts as a TRPV1 agonist, has been proposed as a treatment for reducing hyperreactivity in IR. The hypothesized mechanism of action is via induction of overexpression of TRPV1 channels on the afferent nerves, resulting in a massive Ca ²⁺ influx that results in atrophy of the afferent nerves. Clinical studies demonstrating a therapeutic benefit of capsaicin suggest that nociceptive dysfunction is a strong component of the pathophysiology in this subset of NAR patients.

Dysregulation of Autonomic Responses

Another potential mechanism of NAR may implicate dysregulation of the autonomic system. According to this hypothesis, an imbalance between the parasympathetic and the sympathetic inputs to the nasal mucosa results in the dysregulation of the mucosal vascular tone and glandular secretions. The sympathetic nerves are responsible for one-half of the efferent nasal reflex arc and release norepinephrine and neuropeptide Y, causing vasoconstriction of the nasal vasculature. The parasympathetic nerves, the other half of the efferent nasal reflex arc, release acetylcholine and vasoactive intestinal peptide to increase mucosal glandular secretion and mucus production. In VMR, the severe nasal congestion and profuse watery rhinorrhea seen may represent a parasympathetic-dominant response to the external stimulus. Systemic autonomic dysfunction is more prevalent in patients with VMR compared to controls, and has been likened to the systemic dysautonomic underpinnings of extra-esophageal manifestations of gastroesophageal reflux.

Idiopathic Nonallergic Rhinitis

IR, previously known as vasomotor rhinitis (VMR) or nonallergic rhinopathy, is a subtype of NAR that is a diagnosis of exclusion, when all other forms of rhinitis have been ruled out. IR is the most common subtype of NAR, comprising 71% of NAR diagnoses. Similar to all other forms of rhinitis, IR is characterized by perennial or episodic nasal symptoms, particularly nasal congestion and rhinorrhea. Triggers of IR include temperature changes, smoke, alcohol, perfume, emotional factors, and strong odors, but symptoms may also occur spontaneously. Historically, IR was thought to be solely due to a dysregulation of the autonomic nerve supply, either through excessive parasympathetic activity or reduced sympathetic activity. Interestingly, however, when followed longitudinally, up to one-quarter of IR patients may convert to positive allergy testing and be diagnosed with comorbid AR. Furthermore, some non­allergic patients with IR may demonstrate nasal hyperreactivity to both cold air and histamine, suggesting that a continuum may exist between IR and nonallergic rhinitis with eosinophilic syndrome (NARES).

Nonallergic Rhinitis With Eosinophilic Syndrome

NARES is a disease characterized by inflammatory rhinitis and high eosinophil counts (>10%) in patients who have negative IgE tests. First described in 1981 by Jacobs and colleagues, NARES presents with symptoms suggestive of AR, including recurrent sneezing, pruritus, and watery rhinorrhea. Patients with NARES typically have more severe nasal symptoms compared to those with allergic and other NAR subtypes. Olfactory loss, a predisposition to sleep apnea, and development of nasal polyposis and aspirin sensitivity have all been associated with NARES.

Although the pathophysiology is not well elucidated, the disease process is propagated by migration of eosinophils from blood vessels to the nasal mucosa. Activation of the eosinophilic infiltrate causes chronic nasal mucosal dysfunction and prolonged ciliary clearance, which may progress to the eventual development of nasal polyposis. The theory of entopy has been suggested in NARES, by which symptoms are caused by a localized allergic Th2 disease pathway confined to the nasal mucosa, despite an absence of systemic atopic markers.

Hormonal Rhinitis

NAR can be associated with hormonal changes during pregnancy, puberty, menopause, and the menstrual cycle, as well as certain endocrine disorders, including hypothyroidism and acromegaly. Sex hormones, in particular estrogen, change the nasal physiology through increased glandular activity, increased mucopolysaccharide production, and decreased mucociliary clearance. Increases in blood volume during pregnancy may further enhance vasodilation.

Pregnancy-induced rhinitis is characterized by nasal congestion that typically affects women in the later trimesters of pregnancy and disappears within 2 weeks after delivery. It affects approximately 20% of pregnant women. Smoking is the only known risk factor that increases the likelihood of pregnancy-induced rhinitis. Nasal airway patency can significantly decrease between the first and third trimesters, although the change is not always correlated with women's symptoms of nasal congestion. Pregnancy-induced rhinitis, however, is associated with asthma and decreased quality of life.

Medication-Induced Rhinitis

Medication-induced rhinitis incorporates a broad category of drugs ( Box 39.2 ) and can be further subdivided into three subtypes based on their mechanism of action: local inflammatory type, neurogenic type, and idiopathic type. Aspirin and nonsteroidal antiinflammatory drugs (NSAIDs) are classic examples of medications that induce a local inflammatory response and are known for their association with nasal polyposis and asthma in aspirin-exacerbated respiratory disease (AERD). The neurogenic type of medication-induced rhinitis is associated with α- and β-adrenergic antagonists such as clonidine, guanethidine, and methyldopa, which act to depress the sympathetic tone. The unsuppressed parasympathetic activity as well as the blunting effect of neuropeptide Y by the sympatholytic drugs lead to increased nasal congestion and rhinorrhea. Phosphodiesterase-5 inhibitors such as sildenafil, also act to vasodilate the nasal mucosa through a neurogenic-type of drug-induced rhinitis. The third subtype, the idiopathic type, is associated with antihypertensives (β blockers, angiotensin-converting enzyme [ACE] inhibitors, and calcium channel blockers) as well as hormone replacement therapy and oral contraceptives.

Rhinitis medicamentosa, or rebound rhinitis, is a condition related to the chronic overuse of topical nasal decongestants. The pathophysiology of rhinitis medicamentosa has been attributed to a downregulation of adrenergic receptors on the nasal mucosa due to chronic exposure to topical sympathomimetic agents, with resultant tachyphylaxis. An alternative hypothesis is that chronic exposure to vasoconstrictive agents leads to ischemic changes of the stroma that may manifest as mucosal edema. In rhinitis medicamentosa, the nasal mucosa is often beefy-red, inflamed, and with scant mucus; microscopic examination may show areas of ciliary loss. In other forms of drug-induced rhinitis, by contrast, the nasal mucosa often looks normal.