Rhinitis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Fatimo Biobaku M.B.B.S [2]

Overview

Rhinitis is a term that refers to a heterogeneous group of nasal disorders characterized by the presence of one or more nasal symptoms such as sneezing, nasal itching, rhinorrhea(anterior and posterior), and nasal congestion. It is broadly classified into allergic and nonallergic, although some forms of rhinitis cannot be easily classified into these categories. Allergic rhinitis is a multifactorial disease, its development is influenced by an interplay of genetic and environmental factors. Aeroallergens in the nasal tissue undergo antigen processing, eliciting allergen-specific allergic responses and also promoting the development of allergic airway disease. Proteins and glycoproteins in indoor and outdoor inhalant allergens such as dust mite fecal particles, cockroach residues, animal danders, molds, and pollens are common aeroallergens causing allergic rhinitis. Allergic rhinitis is usually an IgE mediated disease with varying degrees of nasal inflammation. Nonallergic rhinitis is a heterogenous group with poorly defined and understood pathophysiology, and it consists of a variety of conditions which require more research and phenotyping.

Pathophysiology

Clinically relevant anatomy and physiology of the nose

The human nose- It is both a respiratory and an olfactory organ. The nose is a highly vascular organ, the nasal blood vessels receive parasympathetic innervation and dense sympathetic innervation. Parasympathetic nerve stimulation promotes secretion from nasal airway glands and nasal congestion while sympathetic nerve stimulation cause a reduction in nasal blood flow, and significant nasal decongestion of the venous erectile tissues in the nose. The nasal cavity is divided into right and left halves by the nasal septum. The nasal cavity extends from the vestibule to the nasopharynx, and it is generally divided into three parts namely:

• The vestibule- the area which surrounds the external opening to the nasal cavity.
• The olfactory region- located at the apex of the nasal cavity, it is lined by olfactory cells.
• The respiratory region- this is the largest part of the nasal cavity. The turbinates/conchae project from the lateral wall of the nasal cavity, and they promote air filtration, humidification and temperature regulation.The respiratory region is lined by pseudostratified columnar epithelial cells(about 80% of these cells are ciliated). Interspersed within the epithelium are mucus-secreting goblet cells which are necessary for the maintenance of mucociliary clearance. Factors such as dryness and temperature significantly affect the ciliary function of epithelial cells. Ciliary action stops after 8-10mins at 50% relative humidity of inspired air, and after 3-5mins at 30% relative humidity of inspired air. Ciliary activity ceases at temperatures between 7-12⁰C. Significant impairment of ciliary function can also occur due to factors such as environmental exposure to large amounts of wood dust and chromium vapors,tobacco smoke, inhaled gases, locally applied drugs, infection. Ciliary structure changes has been noted in patients with longstanding allergic rhinitis.

The paranasal sinuses- The paranasal sinuses drain into the nasal cavity. The nose and sinuses are contiguous structures, and they share vascular, neuronal and interconnecting anatomic pathways.

Pathogenesis of Allergic Rhinitis

Allergic rhinitis is an IgE mediated disease. Genetic predisposition and environmental factors significantly influence its development. Proteins and glycoproteins (and rarely, glycans) in indoor and outdoor inhalant allergens such as pollens, molds, dust mite fetal particles, coakroach residues, and animal danders, are commonly implicated. The inherent enzymatic proteolytic activity of aeroallergens promote their access to antigen presenting cells by cleaving tight junctions in the airway epithelium and also via activation of receptors on epithelial cells. These activated epithelial cells produce proinflammatory mediators (such as cytokines, chemokines, thymic stromal lymphopoietin) which interact with subepithelial and interepithelial dendritic cells. Adaptive allergic sensitization occurs via the following processes:

• Antigen presenting cells (dendritic cells expressing CD1a and CD11c and macrophages) process nasal allergens in the epithelial mucosa of the nose.
• These antigen presenting cells then present the allergenic peptides by MHC class II molecules to T-cell receptors on naive CD4+ T lymphocytes in regional lymph nodes.
• Costimulatory signals result in the proliferation of allergen-stimulated T-cells into TH2-biased cells which release cytokines such as interleukins(IL-3, IL-4, IL-5, IL-13) and other cytokines.
• These cytokines lead to a cascade of events which promote B-cell isotype switching with subsequent local and systemic allergen-specific IgE antibody production by plasma cells.
• Allergen-specific IgE antibodies then become fixed to the high affinity receptor for IgE on the membranes of mast cells and basophils, rendering them sensitized.

Following sensitization, exposure to specific allergen result in the following:

• Aggregation of receptor-bound IgE molecules interact with the allergen( IgE–allergen interaction) within minutes.
• IgE–allergen interaction result in the degranulation of mast cells and basophils with the release of preformed mediators such as histamine and tryptase, and the rapid de novo generation of other mediators, including cysteinyl leukotrienes (LTC4, LTD4, LTE4) and prostaglandins (primarily PGD2), producing the allergic response which result in itching, sneezing, rhinorrhoea and blockage in the nose.

Mediators and cytokines released during the early response also act on postcapillary endothelial cells, promoting the expression of adhesion molecules(such as intercellular adhesion molecule 1, E-selectin, and vascular cell adhesion molecule 1). These adhesion molecules promote the adherence of circulating leukocytes, such as eosinophils, to endothelial cells. Factors with chemoattractant properties( such as IL-5 for eosinophils) also promote the infiltration of the superficial lamina propria of the mucosa with many eosinophils, some neutrophils and basophils, and eventually CD4+ (TH2) lymphocytes and macrophages. These cells become activated and release more mediators, which in turn activate many of the proinflammatory reactions seen in the immediate response. The role of IgE-mediated reaction in rhinitis and asthma have been further confirmed by the effect of an anti-IgE monoclonal antibody in these diseases.

Microscopic Pathology

Studies of cells infiltrating the nasal mucosa during the pollen season show increment in the amount of various inflammatory cells which correlates with the severity of symptoms and nasal nonspecific hyperactivity.

• Eosinophils are almost always found in the mucosa between nondesquamated epithelial cells, in the submucosa and in nasal secretions.
• Degranulated mast cells are present in increased numbers in the epithelium and the submucosa.
• CD4+ T-cells and Langerhan-like cells (CD1+) are increased in number during the pollen season

Pathogenesis of Nonallergic Rhinitis

Nonallergic rhinitis encompasses a heterogeneous group of nasal conditions with diverse pathophysiology. Unlike allergic rhinitis, nonallergic rhinitis is characterized by periodic, seasonal, persistent or perennial symptoms of rhinitis not resulting from IgE-dependent events. Imbalance in the maintenance of homeostasis between vasoconstriction and vasodilation of nasal vasculature and the secretion of nasal glands by sympathetic and parasympathetic components of the autonomic nervous system contribute to glandular hypersecretion and increased nasal congestion. Neuropeptides secreted by unmyelinated nociceptive C fibers (tachykinins, calcitonin gene-related peptide, neurokinin A, gastrin-releasing peptide) and parasympathetic nerve endings (vasoactive intestinal peptide), have recently been established to be present in the nasal mucosa. Rhinitis can occur via the following mechanism:

1. Exposure to nonallergic triggers result in the activation of Transient Receptor Potential cation channels(TRPV1, TRPA1) on nasal mucosal nerve fibers
2. This results in the release of neuropetides such as Calcitonin Gene-Related Peptide (CGRP)and substance P from sensory nerve endings.
3. These neuropeptides facilitate vasodilation and plasma extravasation, resulting in edema and glandular hypersecretion. It is important to note that the evidence for substance P involvement was extrapolated following the beneficial effect of treatment with capsaicin(known to deplete substance P from sensory nerve endings) in affected patients.
4. These pathophysiologic mechanisms have not been extensively investigated.

Subtypes of nonallergic rhinitis include:

• Vasomotor/idiopathic rhinitis- This is also sometimes referred to as Vasomotor rhinitis|nonallergic rhinopathy because there is a lack of nasal mucosal inflammation. The pathogenesis is unclear although neurosensory abnormalities have been suggested. The nasal mucosa of patients with vasomotor rhinitis is indistinguishable from those of normal subjects. Vasomotor rhinitis is a chronic nasal condition usually without eosinophia. It has been found to be associated with vasospastic disorders such as primary acrocyanosis. Triggers of vasomotor rhinitis include:

1. Climatic changes(e.g humidity, temperature, barometric pressure)
2. Irritants like strong smells (such as perfumes, cooking smells, flowers, and chemical odors), environmental tobacco smoke, pollutants and chemicals
3. Exercise
4. Trauma
5. Emotional
6. Sexual activity

Honeymoon rhinitis - This occurs as a result of sexual activity, and it is a rare trigger of rhinitis. Strong emotions, excitement and anxiety have been proposed as the triggers for honeymoon rhinitis. One of the proposed mechanism for honeymoon rhinitis is the increased parasympathetic activity toward the culmination in orgasm. Release of mast cell mediators following cholinergic stimulation has also been proposed to cause postcoital rhinitis in patients experiencing honeymoon rhinitis.

• Gustatory rhinitis- This is a type of nonallergic rhinitis that occurs following solid/liquid food ingestion. It is due to an abnormal gustatory reflex that is associated with a hyperactive neural system. Ethanol in alcoholic beverages have also been proposed to cause pharmacologic vasodilation. Unilateral/bilateral watery rhinorrhea often occurs within few minutes of ingestion of the implicated food. It is seldom associated with nasal itching/congestion or facial pain. Occasionally, it is associated with a significant impairment in the quality of life of the affected individual. Common triggers of gustatory rhinitis are alcohol, hot and spicy food. Rhinitis from food allergy can also occur but it usually presents with associated gastrointestinal, dermatologic, or systemic manifestations.

• Rhinosinusitis|Infectious rhinitis- Viral infections account for up to 98% of acute infectious rhinitis, and it is the cause of the majority of rhinitis cases in young children. Infectious rhinitis is commonly associated with rhinosinusitis because of the contiguous nature of the nose and sinuses, and often times, there is an overlap in the clinical presentation, which make differentiation between the two diagnosis difficult. Symptoms usually resolve within 7-10 days of onset. Pruritus is not a typical finding in infectious rhinitis.

• Nonallergic rhinitis with eosinophilia syndrome(NARES)-The Pathophysiology of NARES is not well understood, but affected individuals demonstrate chronic eosinophilic inflammation similar to that found in allergic rhinitis. However, unlike allergic rhinitis, the patients lack evidence of allergic disease based on skin testing or serum levels of IgE to environmental allergens. Analysis of nasal cytology often demonstrate more than 20% eosinophils (the range between 5% to more than 20% is recommended by some clinicians for the diagnosis of NARES). Histology of the nasal mucosal biopsy in patients with NARES show mast cells with bound IgE and increased tryptase, identical to that found in allergic rhinitis. Nasal congestion occurs frequently. Other perennial nasal symptoms seen in NARES include; sneezing paroxysms, profuse watery rhinorrhea, nasal pruritus, and occasional Anosmia. It is believed to be a risk factor for nasal polyposis, aspirin sensitivity and obstructive sleep apnea.

Pathogenesis of Occupational Rhinitis

Occupational rhinitis occurs in response to airborne substances in the workplace. It sometimes coexists with occupational asthma. Occupational rhinitis can be triggered via allergic and nonallergic mechanisms.. The pathophysiology of some types of occupational rhinitis is still poorly understood.

Allergic occupational rhinitis- can occur following sensitization to a particular allergen at the workplace, which then results in immunologic response mediated by specific IgE antibodies following re-exposure to the allergen. Small molecular weight chemicals in occupational agents can also act as haptens, and they react with self-proteins in the airway to form complete allergens.

Nonallergic Occupational rhinitis- mechanisms that involve damage to the epithelium, neurokinin release, and nociceptors have been proposed in the pathogenesis.

Different forms of occupational rhinitis have been described in the literature using various names such as:

• Work-related rhinitis- This encompasses rhinitis primarily caused by work exposure(occupational), and work-exacerbated rhinitis.
• Work-exacerbated/work-aggravated rhinitis - Rhinitis concurrently occurs in non-occupational settings, but found to be worsened by occupational exposures.
• Irritant-induced occupational rhinitis - Inflammation of the nasal mucosa is seen without apparent immunologic or allergic basis. It occurs following exposure to chemicals, pesticides, etc
• Corrosive rhinitis - Sometimes described as a type of irritant-induced rhinitis. It has been found to occur following repeated exposures to corrosives such as chromium. Chronic inflammation is seen, which may progress to ulcerations and perforations of the nasal septum.

Pathogenesis of other Rhinitis Syndromes

Hormonally induced rhinitis - This comprises of gestational and menstrual cycle-related rhinitis. Theories have been proposed, however, the pathophysiology is still unclear.

• Gestational/pregnancy-induced rhinitis - defined as rhinitis presenting during pregnancy, and lasting for a duration of at least six weeks. It usually occurs in the second or third trimester(it is not present before pregnancy), and evidence of upper respiratory infection or allergic etiology is absent. The pathophysiology of gestational rhinitis is unknown. However, hormone-induced vascular pooling has been suggested. It is usually associated with significant nasal congestion. Rhinorrhea also frequently occurs. The involvement of the following hormones have been proposed:

1. Placental trophoblastic hormone during pregnancy: Nasal mucosa hypertrophy is believed to occur as a result of the stimulation by the placental trophoblastic hormone.
2. Progesterone: This probably increases nasal vasodilation through the physiologic increase in the circulating blood volume
3. Estrogen may increase histamine receptors in the microvasculature and epithelial cells.

However, the data on the role of these hormones is controversial. Gestational rhinitis usually resolves within two weeks following delivery. Smoking is a recognized risk factor for gestational rhinitis. The association of gestational rhinitis with snoring and obstructive sleep apnea syndrome (and indirectly, preeclampsia) is of clinical importance, and it is gradually getting more attention. Some studies also show an association of gestational rhinitis with gestational hypertension, intrauterine growth restriction and newborns with a lower Apgar score. Women with allergic rhinitis have also been reported to have worsening symptoms during pregnancy.

Drug-induced rhinitis - A number of oral and topical medications have been implicated in the etiology of drug-induced rhinitis. The pathophysiology of drug-induced rhinitis is not fully understood. Prolonged use of some medications such as α-adrenergic decongestant nasal sprays, intranasal cocaine and methamphetamine, have been noted to induce rebound nasal congestion following withdrawal (referred to as rhinitis medicamentosa). Repeated intranasal cocaine and methamphetamine can also result in septal erosion and perforation. Some other drugs known to cause drug-induced rhinitis are medications such as ACE inhibitors, β-blockers, phentolamine, aspirin, NSAIDS, oral contraceptives, phosphodiesterase-5–selective inhibitors. Drug-induced rhinitis can be divided into three types based on the proposed mechanism of action:

1. Local inflammatory type: Medications such as NSAIDS and Aspirin are implicated. Several mechanisms via which these class of drugs cause rhinitis have been proposed. The commonly accepted theory is the induction of acute inflammatory response in the nose via inhibition of the cyclooxygenase-1(cox-1). This leads to a decrease in prostaglandin E₂ (PG E₂) and an increase in cysteinyl leukotrienes production by the lipooxygenase pathway.
2. Neurogenic type: Adrenergic antagonists like Clonidine, Methyldopa and Guanethidine are in this category. These medications down regulate the sympathetic tone via their sympatholytic activity, resulting in nasal congestion and blunted effects of norepinephrine and neuropeptide-Y. Phosphodiesterase-5 inhibitors such as sildenafil appear to worsen the nasal stuffinesss that occurs during sexual activity(honeymoon rhinitis) via its action on the nasal erectile tissues.
3. Idiopathic type

• Rhinitis medicamentosa- It can also be referred to as rebound rhinitis or chemical rhinitis. It is a drug-induced nonallergic rhinitis, usually associated with prolonged use of topical nasal decongestant sprays. It is also occasionally used to describe nasal congestion secondary to oral medications. The pathophysiology is not fully understood, although several theories exist. There is controversial evidence of an association of rhinitis medicamentosa with the preservative; benzalkonium chloride (BKC), which is sometimes used in nasal spray preparations (for decongestants and glucocorticosteroids). Nasal mucosal changes that can be seen in rhinitis medicamentosa include loss of ciliated epithelial cells (this results in reduced mucociliary clearance), squamous cell metaplasia, increased mucus production and goblet cell hyperplasia. The nasal mucosa can appear beefy red on inspection.

Atrophic rhinitis - This is a chronic disease of the nose that is characterized by progresssive atrophy and resorption of the nasal mucosa, and underlying turbinates and bones. Foul-smelling nasal crusts(ozena) occur following the rapid drying of viscid nasal secretions. Abnormal patency of the nasal passages occur as a result of the atrophic changes. Atrophic rhinitis can be either primary or secondary.

• Primary/idiopathic atrophic rhinitis- The exact etiology is still unknown although several theories exist. Primary atrophic rhinitis is more commonly seen in developing countries with warm climates, and infection with Klebsiella ozaenae is most frequently implicated.
• Secondary atrophic rhinitis- This is usually caused by other primary conditions such as recurrent or chronic sinusitis, direct trauma, irradiation or excessive surgical removal of the nasal turbinates(empty nose syndrome), granulomatous nasal infections. It can be confused with rhinitis in the elderly (where structural changes in the connective tissue and vasculature secondary to aging occurs, resulting in rhinitis).

Rhinitis associated with inflammatory-immunologic disorders - This form of rhinitis frequently precedes the overt systemic manifestations of the inflammatory-immunologic disorders.

• Granulomatous infections- Granulomatous nasal lesions with ulceration and formation of crusting, leading to nasal obstruction can occur secondary to certain types of infections. It is important to rule out infections such as tuberculosis, syphilis, leprosy, sporotrichosis, blastomycosis, histoplasmosis and coccidioidomycosis, when ulcerative nasal lesions are seen. Rhinoscleroma, a chronic granulomatous disease caused by Klebsiella rhinoscleromatis, can also result in nasal obstruction via the induction of a polyploid mass within the nasal cavity. Syphilitic infection in pregnant women can also result in congenital syphilitic rhinitis/rhinorrhea (snuffles) in the newborn. Congenital syphilitic rhinitis, however, presents with other manifestations of congenital syphilis such as pseudoparalysis, maculopapular rash, respiratory distress, hemolysis with anemia, jaundice, thrombocytopenia and hepatosplenomegaly. Congenital syphilis can present at birth or during infancy.
• Wegener granulomatosis- This is a systemic autoimmune necrotising vasculitis. Nasal manifestations such as epistaxis, nasal congestion, purulent rhinorrhea and, crusting is common. Erosion and perforation of the nasal septum can occur resulting in a saddle nose deformity.
• Sjogren's syndrome- It is a systemic autoimmune disease where exocrine gland destruction leads to generalized dryness. Nasal manifestations include granuloma formation, nasal dryness, epistaxis, nasal congestion. It can occasionally result in rhinosinusitis.
• Churg-Strauss syndrome/allergic granulomatosis- This is more appropriately known as eosinophilic granulomatosis with polyangiitis. It is a systemic autoimmune vasculitis associated with systemic granuloma formation. It affects medium and small vessels. It frequently manifests as asthma.. Other manifestations include chronic rhinosinusitis, nasal polyposis. Eosinophilia is commonly seen.
• Amyloidosis- Amyloid deposition in the nasopharynx can result in rhinitis symptoms such as nasal obstruction and postnasal discharge
• Midline granuloma- Midline granuloma usually occur in the nasal cavity and it is often lethal. It can present with symptoms of rhinitis such as nasal obstruction, rhinorrhea. A strong association of midline granuloma with EBV infection exists.
• Sarcoidosis- This is an Immune mediated granulomatous, chronic inflammatory disease. It is a rare cause of rhinitis.
• Relapsing polychondritis- This is a rare systemic autoimmune inflammatory disease. The features are highly variable and include chondritis in multiple sites of the body, inflammatory arthritis, ocular inflammation, etc. Nasal manifestations include nasal congestion, crusting, rhinorrhea, epistaxis.