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

Pathophysiology

Clinically relevant anatomy and physiology of the nose[1][2]

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. 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 7-12”C. 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.

Pathophysiology of Allergic Rhinitis[3][4][5]

Overview

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, glycoproteins ( and rarely, glycans ) 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. It is usually an IgE mediated disease with varying degrees of nasal inflammation.

Pathophysiology

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, skewing T-cell development and adaptive allergic sensitization. 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 Tcells into TH2-biased cells which release 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. On exposure to specific allergen, these aggregation of receptor-bound IgE molecules interact with the allergen( IgE–allergen interaction) within minutes. This 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. 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 are increased in number during the pollen season and there is an increase in Langerhan-like cells (CD1+) during the pollen season in allergic patients.


Pathophysiology of Nonallergic Rhinitis

overview

Nonallergic rhinitis is a heterogenous group that is poorly defined and understood, and it consists of a variety of conditions which require more research and phenotyping.[6]

Pathophysiology

Nonallergic rhinitis- It encompasses a heterogeneous group of nasal conditions with diverse pathophysiology.[7] Unlike allergic rhinitis, nonallergic rhinitis is characterized by periodic, seasonal, persistent or perennial symptoms of rhinitis not resulting from IgE-dependent events.[7][8] 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.[9][9] 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 following exposure to nonallergic triggers, via activation of Transient Receptor Potential cation channels(TRPV1, TRPA1) on nasal mucosal nerve fibers, which result in the release of neuropetides such as Calcitonin Gene-Related Peptide (CGRP)and substance P from sensory nerve endings.[9] These neuropeptides facilitate vasodilation and plasma extravasation, resulting in edema and glandular hypersecretion.[9] 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.[9] These pathophysiologic mechanisms have not been extensively investigated.[9] Subtypes of nonallergic rhinitis include:

  • Vasomotor/idiopathic rhinitis- This is also sometimes referred to as nonallergic rhinopathy because there is a lack of nasal mucosal inflammation.[10] The pathogenesis is unclear although neurosensory abnormalities have been suggested.[11][10] The nasal mucosa of patients with vasomotor rhinitis is indistinguishable from those of normal subjects.[11] Vasomotor rhinitis is a chronic nasal condition usually without eosinophia.[8] It has been found to be associated with vasospastic disorders such as primary acrocyanosis.[12] Triggers of vasomotor rhinitis include:[10][13][14]
  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[15]
  • Gustatory rhinitis- This is a type of nonallergic rhinitis that occurs following solid/liquid food ingestion.[8][16][17] It is due to an abnormal gustatory reflex that is associated with a hyperactive neural system.[16] Ethanol in alcoholic beverages have also been proposed to cause pharmacologic vasodilation.[4] Unilateral/bilateral watery rhinorrhea often occurs within few minutes of ingestion of the implicated food.[17] It is seldom associated with nasal itching/congestion or facial pain.[17] Occasionally, it is associated with a significant impairment in the quality of life of the affected individual.[16] Common triggers of gustatory rhinitis are alcohol, hot and spicy food.[17][8] Rhinitis from food allergy can also occur but it usually presents with associated gastrointestinal, dermatologic, or systemic manifestations.[8]


  • 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.[8] 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.[18] Symptoms usually resolve within 7-10 days of onset.[18] Pruritus is not a typical finding in infectious rhinitis.[4]


  • 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.[19][4] 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).[19][4] 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.[4] Nasal congestion occurs frequently.[4] Other perennial nasal symptoms seen in NARES include; sneezing paroxysms, profuse watery rhinorrhea, nasal pruritus, and occasional Anosmia.[4] It is believed to be a risk factor for nasal polyposis, aspirin sensitivity and obstructive sleep apnea.[19][4]

Pathophysiology of Occupational Rhinitis

Occupational rhinitis occurs in response to airborne substances in the workplace.[8] It can be triggered via allergic and nonallergic mechanisms.[8][18]. The pathophysiology of some types of occupational rhinitis is still poorly understood.[18] The allergic mechanism can occur as a result of small molecular weight chemicals in occupational agents which act as haptens, and they react with self-proteins in the airway to form complete allergens.[4] Occupational rhinitis sometimes coexists with occupational asthma.[8] Different types 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.[18]
  • Work-exacerbated/work-aggravated rhinitis[8][18] - Rhinitis concurrently occurs in non-occupational settings, but found to be worsened by occupational exposures.
  • Irritant-induced occupational rhinitis[20][18] - Inflammation of the nasal mucosa is seen without apparent immunologic or allergic basis. It occurs following exposure to chemicals, pesticides, etc
  • Corrosive rhinitis[18][20] - 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.

Pathophysiology of other Rhinitis Syndromes

Hormonally induced rhinitis - This comprises of gestational and menstrual cycle-related rhinitis.

  • Gestational/pregnancy-induced rhinitis - defined as rhinitis/nasal obstruction presenting during pregnancy, and lasting for a duration of at least six weeks.[21] 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.[21] The pathophysiology of gestational rhinitis is unknown.[21] However, hormone-induced vascular pooling as been suggested.[4][21] It is usually associated with significant nasal congestion.[8][4] It is believed that hypertrophy of the nasal mucosa occurs via stimulation by the placental trophoblastic hormone during pregnancy.[21] Estrogen and progesterone may also play a role.[21] Progesterone probably increases nasal vasodilation through the physiologic increase in the circulating blood volume, while estrogen may increase histamine receptors in the microvasculature and epithelial cells.[21] However, the data on the role of these hormones is controversial.[21] Gestational rhinitis usually resolves within two weeks following delivery.[4][8][21] 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.[21] Some studies also show an association of gestational rhinitis with gestational hypertension, intrauterine growth restriction and newborns with a lower Apgar score.[21] Women with allergic rhinitis have also been reported to have worsening symptoms during pregnancy.[4]

Drug-induced rhinitis[4][22] - 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.

  • 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 decongestants. It is sometimes 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.


References

  1. ↑ Jones N (2001). "The nose and paranasal sinuses physiology and anatomy". Adv Drug Deliv Rev. 51 (1–3): 5–19. PMID 11516776.
  2. ↑ Watelet JB, Van Cauwenberge P (1999). "Applied anatomy and physiology of the nose and paranasal sinuses". Allergy. 54 Suppl 57: 14–25. PMID 10565476.
  3. ↑ Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ, Togias A; et al. (2008). "Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen)". Allergy. 63 Suppl 86: 8–160. doi:10.1111/j.1398-9995.2007.01620.x. PMID 18331513 PMID: 18331513 Check |pmid= value (help).
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 Dykewicz MS, Hamilos DL (2010). "Rhinitis and sinusitis". J Allergy Clin Immunol. 125 (2 Suppl 2): S103–15. doi:10.1016/j.jaci.2009.12.989. PMID 20176255.
  5. ↑ Sin B, Togias A (2011). "Pathophysiology of allergic and nonallergic rhinitis". Proc Am Thorac Soc. 8 (1): 106–14. doi:10.1513/pats.201008-057RN. PMID 21364228.
  6. ↑ Sin B, Togias A (2011). "Pathophysiology of allergic and nonallergic rhinitis". Proc Am Thorac Soc. 8 (1): 106–14. doi:10.1513/pats.201008-057RN. PMID 21364228.
  7. ↑ 7.0 7.1 Sin B, Togias A (2011). "Pathophysiology of allergic and nonallergic rhinitis". Proc Am Thorac Soc. 8 (1): 106–14. doi:10.1513/pats.201008-057RN. PMID pmid21364228 Check |pmid= value (help).
  8. ↑ 8.00 8.01 8.02 8.03 8.04 8.05 8.06 8.07 8.08 8.09 8.10 8.11 Wallace DV, Dykewicz MS, Bernstein DI, Blessing-Moore J, Cox L, Khan DA; et al. (2008). "The diagnosis and management of rhinitis: an updated practice parameter". J Allergy Clin Immunol. 122 (2 Suppl): S1–84. doi:10.1016/j.jaci.2008.06.003. PMID 18662584.
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 Baroody FM (2016). "Nonallergic Rhinitis: Mechanism of Action". Immunol Allergy Clin North Am. 36 (2): 279–87. doi:10.1016/j.iac.2015.12.005. PMID 27083102.
  10. ↑ 10.0 10.1 10.2 Kaliner MA (2011). "Nonallergic rhinopathy (formerly known as vasomotor rhinitis)". Immunol Allergy Clin North Am. 31 (3): 441–55. doi:10.1016/j.iac.2011.05.007. PMID 21737036.
  11. ↑ 11.0 11.1 Sin B, Togias A (2011). "Pathophysiology of allergic and nonallergic rhinitis". Proc Am Thorac Soc. 8 (1): 106–14. doi:10.1513/pats.201008-057RN. PMID 21364228.
  12. ↑ Kurklinsky AK, Miller VM, Rooke TW (2011). "Acrocyanosis: the Flying Dutchman". Vasc Med. 16 (4): 288–301. doi:10.1177/1358863X11398519. PMC 3156491. PMID 21427140.
  13. ↑ Sacre-Hazouri JA (2012). "[Chronic rhinosinusitis in children]". Rev Alerg Mex. 59 (1): 16–24. PMID 24007929.
  14. ↑ Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ, Togias A; et al. (2008). "Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen)". Allergy. 63 Suppl 86: 8–160. doi:10.1111/j.1398-9995.2007.01620.x. PMID 18331513.
  15. ↑ Segal S, Shlamkovitch N, Eviatar E, Berenholz L, Sarfaty S, Kessler A (1999). "Vasomotor rhinitis following trauma to the nose". Ann Otol Rhinol Laryngol. 108 (2): 208–10. PMID 10030243.
  16. ↑ 16.0 16.1 16.2 Georgalas C, Jovancevic L (2012). "Gustatory rhinitis". Curr Opin Otolaryngol Head Neck Surg. 20 (1): 9–14. doi:10.1097/MOO.0b013e32834dfb52. PMID 22143339.
  17. ↑ 17.0 17.1 17.2 17.3 Jovancevic L, Georgalas C, Savovic S, Janjevic D (2010). "Gustatory rhinitis". Rhinology. 48 (1): 7–10. doi:10.4193/Rhin07.153. PMID 20502728.
  18. ↑ 18.0 18.1 18.2 18.3 18.4 18.5 18.6 18.7 Romeo, Jonathan; Dykewicz, Mark (2014). "Chapter 9:Differential Diagnosis of Rhinitis and Rhinosinusitis". Diseases of the Sinuses. Springer New York. pp. 133–152. ISBN 978-1-4939-0265-1.
  19. ↑ 19.0 19.1 19.2 Ellis AK, Keith PK (2007). "Nonallergic rhinitis with eosinophilia syndrome and related disorders". Clin Allergy Immunol. 19: 87–100. PMID 17153009.
  20. ↑ 20.0 20.1 Nozad CH, Michael LM, Betty Lew D, Michael CF (2010). "Non-allergic rhinitis: a case report and review". Clin Mol Allergy. 8: 1. doi:10.1186/1476-7961-8-1. PMC 2835646. PMID 20181075.
  21. ↑ 21.00 21.01 21.02 21.03 21.04 21.05 21.06 21.07 21.08 21.09 21.10 Caparroz FA, Gregorio LL, Bongiovanni G, Izu SC, Kosugi EM (2016). "Rhinitis and pregnancy: literature review". Braz J Otorhinolaryngol. 82 (1): 105–11. doi:10.1016/j.bjorl.2015.04.011. PMID 26601995.
  22. ↑ Doshi J (2009). "Rhinitis medicamentosa: what an otolaryngologist needs to know". Eur Arch Otorhinolaryngol. 266 (5): 623–5. doi:10.1007/s00405-008-0896-1. PMID 19096862.

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