Chronic Inflammation

It is well established that in allergic rhinitis, there is an influx of inflammatory cells and mediators into the nasal mucosa as they respond to the offending antigen. These mediators result in venous engorgement, increased nasal secretions and tissue edema, causing the classic symptoms of nasal congestion, sneezing, rhinorrhea, and pruritus. There are likely similarities in nonallergic rhinitis patients as well, though the relation is not as clear-cut.

Powe and colleagues examined inferior turbinectomy specimens from allergic, nonallergic, and normal patients. They found significantly more nasal mucosa mast cells and eosinophils in the rhinitic patients compared with the normal individuals. They concluded that idiopathic and allergic rhinitic mucosa show similarities in their inflammatory infiltrate suggesting that both groups share a similar cellular immunopathology.

In contrast, a study by van Rijswijk and colleagues found no difference in nasal mucosal lymphocytes, antigen-presenting cells, eosinophils, macrophages, monocytes, mast cells, and other IgE-positive cells between idiopathic rhinitis patients and controls.

Neurogenic Mechanisms

The sensory nerves of the nose arise from the olfactory nerves as well as from the ophthalmic (through the ethmoidal nerve) and maxillary (through the nasopalatine nerve) branches of the trigeminal nerve. In the neurogenic model of rhinitis, exaggerated responses to environmental or endogenous stimuli occur because neural activity is upregulated as a result of a pathologic process, primarily of an inflammatory nature. In this case, a stimulus of average intensity generates exaggerated symptoms. This phenomenon is known as neural hyperresponsiveness and is believed to play an important role in the clinical presentation of nasal disease.

The neural regulation of the upper airways is complex and consists of a number of interacting nervous systems. Sensory, parasympathetic, and sympathetic nerves regulate epithelial, vascular, and glandular processes in the nasal mucosa. The sensory, parasympathetic, and sympathetic neural systems contain heterogeneous populations of nerve fibers with unique combinations of neurotransmitters and neuropeptides.

In 1959, Malcomson stated that idiopathic rhinitis was caused by an autonomic imbalance. Normally, increased sympathetic tone in nasal blood vessels leads to vasoconstriction. Underactivity of the sympathetic nervous system leads to nasal obstruction. Overactivity of the parasympathetic system also leads to rhinorrhea.

In addition, perivascular and intraepithelial nonadrenergic, noncholinergic, sensory nerve fibers contain neuropeptides. These neuropeptides are locally released from peptidergic neurons (unmyelinated C-fibers or “pain fibers”) in the nasal mucosa after activation by nonspecific stimuli, and can be responsible for the symptoms of idiopathic rhinitis.

Progression to Allergic Rhinitis

Patients diagnosed with NAR typically have persistent symptoms, yet they are generally not followed up with further allergy management. Rondon and colleagues studied patients diagnosed with nonallergic rhinitis on the basis of rhinitis symptoms and negative skin prick testing and negative serum specific IgE on initial testing. They were reevaluated 3 to7 years later with clinical questionnaires, spirometry, skin prick testing, and measurement of serum-specific IgE to common aeroallergens. They found that patients with NAR generally experienced worsening disease (52%), with an increase in the persistence (12%), severity of nasal symptoms (9%), and new comorbidities (24%) over time. The most frequent comorbidities at reevaluation were asthma (increasing from 32% to 55%) and conjunctivitis (from 28% to 43%), followed by chronic rhinosinusitis. Sensitization to aeroallergens not present at the initial evaluation was detected by means of skin prick testing, serum-specific IgE measurement, or both in 24% of the patients. They concluded that NAR may progress to AR over time and recommended that these patients be periodically reevaluated for allergy.

Allergic Rhinitis

Allergic rhinitis is the most common type of rhinitis. It can be categorized into three basic subgroups: seasonal, perennial, and occupational. IgE mediates immunologic responses to different allergens. Tree, grass, and weed pollens generally cause seasonal symptoms. Mold spores may cause seasonal and perennial symptoms. Indoor allergens such as dust mites, pet dander, and molds usually cause perennial symptoms. Occupational rhinitis is triggered by exposure to allergens or irritants in the workplace.

Allergic rhinitis symptoms include early and late responses. Seasonal or intermittent allergy exposures yield classic “acute phase” symptoms such as pruritus, sneezing, watery rhinorrhea, and acute conjunctivitis. On the other hand, perennial antigens such as cat dander or dust mite antigen can yield a more subtle presentation, with year-round “late-phase” symptoms such as congestion and rhinorrhea. Seasonal and perennial allergic rhinitis can be associated with systemic symptoms, including malaise, weakness, and fatigue. Patients with seasonal and perennial allergic rhinitis also may have asthma and eczema. Inasmuch as classic acute phase allergic symptoms may be blunted with constant antigen exposure, allergy testing may be beneficial in cases with only the more subtle late phase symptoms.

Hormone-related Rhinitis

Hormone-related rhinitis has been described in multiple disease processes as well as physiologic states. A neurogenic mechanism is proposed but is unclear. Disturbances in thyroid hormone (mainly hypothyroidism) and growth hormone (acromegaly) may have prominent nasal congestion and rhinorrhea. Estrogen and progesterone assert at least part of their effects on vascular smooth muscle, and hormonal rhinitis can develop during the menstrual cycle, puberty, or more commonly pregnancy. Pregnancy-induced rhinitis is probably the most common and well-known form of hormone-related rhinitis. It is diagnosed in a pregnant patient with rhinitis lasting 6 or more weeks without other causative agents, which disappears after delivery. Estrogen levels are correlated with the severity of rhinitis symptoms and are the most severe in the second trimester.

Medication-related Rhinitis

Medication-induced rhinitis is related to the neurogenic mechanism or local inflammatory effects of the offending agent and can be difficult to diagnose given the broad range of drugs available to patients. Broad categories of medications include the antihypertensives, antidepressants, psychotropics, phosphodiesterase type 5 inhibitors (eg, sildenafil, vardenafil), and antiinflammatories. Many of these medications act at receptors that are ubiquitous throughout the body, including the nasal mucosa. The antiinflammatories exert a local effect and have a well-known mechanism of increased leukotriene production, leading to asthma and reactive airway disease in susceptible patients. This is termed aspirin-exacerbated respiratory disease (AERD).

Intranasal decongestants such as oxymetazoline deserve specific mentioning. Extended use of topical α-adrenergic medications may result in rebound nasal congestion, termed “rhinitis medicamentosa.” These patients also have characteristic-appearing erythematous nasal mucosa, which may be prone to bleed, as opposed to other drug-induced rhinitis. Cocaine can act in a similar mechanism, resulting in rebound congestion. As mentioned previously, exogenous estrogen or progesterone agents can lead to rhinitis, which is reversible with discontinuation of medications.

Irritant-related Rhinitis

Irritant-related rhinitis involves an occupational or environmental exposure that causes symptoms. In this case, the agent causes an irritation rather than an allergic response. A spatial and temporal relationship of the exposure and associated symptoms is usually necessary to make the diagnosis, although sometimes it can be a difficult part of the history to assess. Some of the more common culprits are industrial chemicals, wood dust, tobacco smoke, paint fumes, hairspray, perfumes, and other fragrances. The diagnosis can be further strengthened by concurrent lower respiratory symptoms. Confirmation can be performed with a nasal provocation test under a controlled setting in clinic. Environmental exposures, including weather or pressure changes, air pollution, cleaning agents, exercise, or even emotional situations, have been described. Ingestion of foods causing rhinitis characterized primarily by profuse, clear anterior rhinorrhea is termed gustatory rhinitis and is more common with spicy foods.

Atrophic Rhinitis

Atrophic rhinitis is characterized by atrophy of the nasal mucosa, including mucus glands and nerves. It can be primary or secondary and is due to the replacement of the normal ciliated columnar epithelium of the nasal mucosa by stratified squamous epithelium. Primary atrophic rhinitis can occur as the result of aging, heredity, infection, or even nutritional deficiencies. In Western civilization, the most common risk factor for primary atrophic rhinitis is age, with the majority of patients being diagnosed after 40. Secondary atrophic rhinitis can be due to surgery (excessive removal of turbinates), radiation, longstanding cocaine abuse, or infections (eg, leprosy, syphilis, rhinoscleroma). These factors may cause destruction of nasal structures leading to atrophic changes. With chronic changes in airflow patterns and mucous secretion, there is decreased stimulation to the olfactory mucosa as well as the trigeminal afferents leading to a sense of congestion. In addition to rhinitis, patients may present with foul smelling crusts or nasal obstruction with sensations of pain and pressure.

Systemic Diseases

Numerous systemic diseases can affect the nose, resulting in rhinitis. Granulomatous diseases (Wegener granulomatosis, sarcoidosis, Churg-Strauss syndrome), autoimmune diseases (lupus, Sjögren syndrome, pemphigoid), cystic fibrosis, tuberculosis, and ciliary dyskinesia all can have nasal manifestations of rhinitis. When a patient’s symptoms are not controlled with maximal medical management or the nasal mucosa demonstrates unusual features such as scarring (pemphigoid), excessive bleeding, and crusting (Wegener), or submucosal cobblestoning (sarcoidosis), other systemic causes must be considered.

Signs of granulomatous disease include persistent inflammation and crusting (Wegener), ulceration, nasal masses, submucosal nodules or cobblestoning (sarcoid), extranasal manifestations, and systemic symptoms. Autoimmune diseases can involve the complex process of antigen-antibody interaction in the nose and may result in mucosal ulceration (pemphigoid, lupus), dryness and crusting (Sjögren), and recurrent infections. Sinonasal involvement in cystic fibrosis varies with the mutation status of the patient. Nasal polyps are present in most patients with the most common mutation ΔF508 and is frequently associated with the presence of bacterial biofilm infections, usually Staph aureus or Pseudomonas . Tuberculosis commonly affects the nasopharynx and can result in nasal inflammation and rhinorrhea. Primary ciliary dyskinesia results in nasal symptoms as the patient cannot clear the mucus produced. It should be suspected in patients with stagnant clear secretions on the floor of the nose. The diagnosis can be confirmed with a mucociliary transport saccharine test.

NARES

NARES exhibits symptomatology similar to allergic rhinitis (nasal congestion, sneezing, rhinorrhea, nasal and ocular pruritus), but allergy testing is negative. A distinguishing feature of NARES is the presence of eosinophils, usually 10% to 20% on nasal smears. Although the overactivation of mast cells in the setting of chronic inflammation plays a role in the development of NARES, there is a lack of understanding of the exact pathophysiology. NARES patients can develop nasal polyposis and aspirin sensitivity, but this is not always the case. NARES has also been associated with the severity of obstructive sleep apnea. The diagnosis is made by history, physical examination, and negative serologic or skin testing, and is confirmed by the presence of prominent eosinophilia within the nasal mucosa on cytology. On physical examination, the turbinates of NARES patients often appear pale and boggy. These patients are more responsive to treatment with nasal corticosteroids compared with other patients with nonallergic rhinitis. The differentiation is important to aid in adequate symptom relief.

Idiopathic Rhinitis

Idiopathic rhinitis (aka vasomotor rhinitis) should be a diagnosis of exclusion after an exhaustive history and physical examination. The pathogenesis of this condition is unclear. Increased sensitivity to environmental factors (eg, climate change, pollution, strong odors, perfumes) may trigger symptoms. This is the most common diagnosis within the subtypes of nonallergic rhinitis. On examination of nasal cytology, there is typically an absence of eosinophils, plasma cells, and mast cells compared with allergic rhinitis. Without typical causative factors, vasomotor rhinitis is thought to be due to an imbalance of the neurogenic mechanisms described previously.