European Archives of Oto-Rhino-Laryngology

, Volume 252, Supplement 1, pp S27–S32

Nonallergic rhinitis Pathophysiology and models for study

  • G. Philip
  • A. G. Togias
Review Article


Nonallergic rhinitis is a diagnosis of exclusion which is given to patients who suffer perennial nasal congestion, rhinorrhea, and/or sneezing with no identifiable allergic etiology. Because there is still no clear understanding of the pathophysiology, it is possible that a number of different disease processes may be included within this clinically defined entity. This report does not attempt to present an overall discussion of the clinical approaches to patients with nonallergic rhinitis. Instead, an outline is presented of various research approaches which may be used in its study. A number of nasal provocation models using nonallergic stimuli are available for application in the laboratory. These include intranasal methacholine challenges, intranasal histamine challenges, nasal inhalation of cold dry air, and intranasal capsaicin challenges. These models provide certain insights into mechanisms of nonallergic hyper-responsiveness. An additional approach to the study of nonallergic rhinitis is to examine available therapies, allowing the clinician to evaluate various pathways of importance in the disease process. These approaches provide a certain understanding of this common but perplexing entity, although further study is still required.

Key words

Nonallergic rhinitis Human model systems Methacholine challenges Histamine challenges Allergen challenges Capsaicin challenges 


  1. 1.
    Anderson SD, Togias A (1995) Dry air and hyperosmolar challenge in asthma and rhinitis. In: Busse WW, Holgate S (eds) Asthma and rhinitis. Blackwell, Oxford pp 1178–1195Google Scholar
  2. 2.
    Barnes PJ (1986) Asthma as an axon reflex. Lancet I: 242–244CrossRefGoogle Scholar
  3. 3.
    Baroody FM, Wagenmann M, Naclerio RM (1993) Comparison of the secretory response of the nasal mucosa to methacholine and histamine. J Appl Physiol 74: 2661–2671PubMedGoogle Scholar
  4. 4.
    Bascom R, Kagey-Sobotka A, Proud D (1991) Effect of intranasal capsaicin on symptoms and mediator release. J Pharmacol Exp Ther 259: 1323–1327PubMedGoogle Scholar
  5. 5.
    Baumgarten CR, Nichols RC, Naclerio RM, Lichtenstein LM, Norman PS, Proud D (1986) Plasma kallikrein during experimentally induced allergic rhinitis: role of kinin formation and contribution to TAME-esterase activity in nasal secretions. J Immunol 137:977–982PubMedGoogle Scholar
  6. 6.
    Bedard PM, Jobin M, Clement L, Mourad W, Hebert J (1989) Evaluation of nonspecific nasal reactivity to histamine during and after natural ragweed pollen exposure. Am J Rhinol 3: 211–215Google Scholar
  7. 7.
    Borum P (1979) Nasal methacholine challenge. A test for the measurement of nasal reactivity. J Allergy Clin Immunol 63: 253–257PubMedCrossRefGoogle Scholar
  8. 8.
    Cauna N, Hinderer KH, Wentges RT (1969) Sensory receptor organs of the human nasal respiratory mucosa. Am J Anat 124:187–210PubMedCrossRefGoogle Scholar
  9. 9.
    Cruz AA, Naclerio RM, Lichtenstein LM, Togias AG (1990) Further support for the role of hypertonicity on mast cell activation during nasal dry air reactions (abstract). Clin Res 38: 484AGoogle Scholar
  10. 10.
    Cruz AA, Naclerio RM, Proud D, Togias A (1991) Epithelial cell detachment is observed during the nasal reaction to cold, dry air (CDA) (abstract). J Allergy Clin Immunol 87:147CrossRefGoogle Scholar
  11. 11.
    Cruz AA, Togias AG, Lichtenstein LM, Kagey-Sobotka A, Proud D, Naclerio RM (1991) Steroid-induced reduction of histamine release does not alter the clinical nasal response to cold, dry air. Am Rev Respir Dis 143:761–765PubMedGoogle Scholar
  12. 12.
    Druce HM, Wright RH, Kossoff D, Kaliner MA (1985) Cholinergic nasal hyperreactivity in atopic subjects. J Allergy Clin Immunol 76: 445–452PubMedCrossRefGoogle Scholar
  13. 13.
    Gamse R, Leeman SE, Holtzer P, Lembeck F (1981) Differential effects of capsaicin on the content of somatostatin, subtance P, and neurotensin in the nervous system of the rat. Naunyn-Schmiedeberg's Arch Pharmacol 317: 140–148CrossRefGoogle Scholar
  14. 14.
    Geppetti P, Fucso BM, Marabini S, Maggi CA, Fanciullacci M, Sicuteri F (1988) Secretion, pain and sneezing induced by the application of capsaicin to the nasal mucosa in man. Br J Pharmacol 93:509–514PubMedGoogle Scholar
  15. 15.
    Holtzer P (1991) Capsaicin: cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacol Rev 43:143–201Google Scholar
  16. 16.
    Incaudo G, Schatz M, Yamamoto F, Mellon M, Crepea S, Johnson JD (1980) Intranasal flunisolide in the treatment of perennial rhinitis: correlation with immunologic parameters. J Allergy Clin Immunol 65:41–49PubMedCrossRefGoogle Scholar
  17. 17.
    Konno A, Togawa K, Fujiwara T (1983) The mechanisms involved in onset of allergic manifestation on the nose. Eur J Respir Dis 64:155–166Google Scholar
  18. 18.
    LaCroix JS, Buvelot JM, Polla BS, Lundberg JM (1991) Improvement of symptoms of non-allergic chronic rhinitis by local treatment with capsaicin. Clin Exp Allergy 21:595–600PubMedCrossRefGoogle Scholar
  19. 19.
    Laitinen A (1985) Ultrastructural organisation of intraepithelial nerves in the human airway tract. Thorax 40:488–492PubMedGoogle Scholar
  20. 20.
    Lundberg JM, Saria A (1983) Capsaicin-induced desensitization of airway mucosa to cigarette smoke, mechanical, and chemical irritants. Nature 302: 251–253PubMedCrossRefGoogle Scholar
  21. 21.
    Lundblad L (1984) Protective reflexes and vascular effects in the nasal mucosa elicited by activation of capsaicin-sensitive substance P-immunoreactive trigeminal neurons. Acta Physiol Scand [Suppl] 529: 1–42Google Scholar
  22. 22.
    Mackay IS (1993) Surgical treatment. In: Mygind N, Naclerio RM (eds) Allergic and non-allergic rhinitis: clinical aspects. Munksgaard, Copenhagen, pp 149–152Google Scholar
  23. 23.
    Maggi CA (1991) Capsaicin and primary afferent neurons: from basic science to human therapy? J Auton Nerv Syst 33: 1–14PubMedCrossRefGoogle Scholar
  24. 24.
    Marabini S, Ciabatti PC, Polli G, Fusco BM, Geppetti P (1991) Beneficial effects of intranasal applications of capsaicin in patients with vasomotor rhinitis. Eur Arch Otorhinolaryngal 248:191–194Google Scholar
  25. 25.
    McDonald DM (1992) Infections intensify neurogenic plasma extravasation in the airway mucosa. Am Rev Respir Dis 146:S40-S44PubMedGoogle Scholar
  26. 26.
    Mullarkey MF (1981) The classification of nasal disease: an opinion. J Allergy Clin Immunol 67:251–252PubMedCrossRefGoogle Scholar
  27. 27.
    Mygind N (1979) Nasal allergy, 2nd edn. Blackwell, OxfordGoogle Scholar
  28. 28.
    Philip G, Jankowski R, Baroody FM, Naclerio RM, Togias AG (1993) Reflex activation of nasal secretion by unilateral inhalation of cold dry air. Am Rev Respir Dis 148:1616–1622PubMedGoogle Scholar
  29. 29.
    Philip G, Baroody FM, Proud D, Naclerio RM, Togias AG (1995) The human nasal response to capsaicin. J Allergy Clin Immunol (in press)Google Scholar
  30. 30.
    Proud D, Bailey GS, Naclerio RN, Reynolds CJ, Cruz AA, Eggleston PA, Lichtenstein L, Togias AG (1992) Tryptase and histamine as markers to evaluate mast cell activation during the responses to nasal challenge with allergen, cold, dry air, and hyperosmolar solutions. J Allergy Clin Immunol 89:1098–1110PubMedCrossRefGoogle Scholar
  31. 31.
    Rajakulasingam K, Polosa R, Lau LCK, Church MK, Holgate ST, Howarth PH (1992) Nasal effects of bradykinin and capsaicin: influence on plasma protein leakage and role of sensory neurons. J Appl Physiol 72:1418–1424PubMedGoogle Scholar
  32. 32.
    Raphael GD, Meredith SD, Baraniuk JN, Druce HM, Banks SM, Kaliner MA (1989) The pathophysiology of rhinitis. II. Assessment of the sources of protein in histamine-induced nasal secretions. Am Rev Respir Dis 139:791–800PubMedGoogle Scholar
  33. 33.
    Raphael GD, Baraniuk IN, Kaliner MA (1991) How and why the nose runs. J Allergy Clin Immunol 87:457–467PubMedCrossRefGoogle Scholar
  34. 34.
    Secher C, Kirkegaard J, BorumP, Maansson A, Osterhammel P, Mygind N (1982) Significance of HI and HZ receptors in the human nose: rationale for topical use of combined antihistamine preparations. J Allergy Clin Immunol 70:211–218PubMedCrossRefGoogle Scholar
  35. 35.
    Small P, Black M, Frenkiel S (1982) Effects of treatment with beclomethasone dipropionate in subpopulations of perennial rhinitis patients. J Allergy Clin Immunol 70:178–182PubMedCrossRefGoogle Scholar
  36. 36.
    Stjärne P, Lundblad L, Lundberg JM, Änggård A (1989) Capsaicin and nicotine-sensitive afferent neurones and nasal secretion in healthy human volunteers and in patients with vasomotor rhinitis. Br J Pharmacol 96:693–701PubMedGoogle Scholar
  37. 37.
    Stjärne P, LaCroix JS, Änggård A, Lundberg JM (1991) Compartment analysis of vascular effects of neuropeptides and capsaicin in the pig nasal mucosa. Acta Physiol Scand 141:335–342PubMedCrossRefGoogle Scholar
  38. 38.
    Stjärne P, Lundblad L, Änggård A, Lundberg JM (1991) Local capsaicin treatment of the nasal mucosa reduces symptoms in patients with nonallergic nasal hyperreactivtiy. Am J Rhinol 5:145–151Google Scholar
  39. 39.
    Togias A (1990) Age relationships and clinical features of nonallergic rhinitis (abstract). J Allergy Clin Immunol 85:182Google Scholar
  40. 40.
    Togias A (1993) Nonallergic rhinitis. In: Mygind N, Naclerio RM (eds) Allergic and nonallergic rhinitis: clinical aspects. Munksgaard, Copenhagen, pp 159–166Google Scholar
  41. 41.
    Togias AG, Naclerio RM, Proud D, Fish JE, Adkinson NF Jr, Kagey-Sobotka A, Norman PS, Lichtenstein LM (1985) Nasal challenge with cold, dry air results in release of inflammatory mediators: possible mast cell involvement. J Clin Invest 76:1375–1381PubMedGoogle Scholar
  42. 42.
    Togias AG, Naclerio RM, Peters SP, Nimmagadda I, Proud D, Kagey-Sobotka A, Adkinson NF Jr, Norman PS, Lichtenstein LM (1986) Local generation of sulfidopeptide leukotrienes upon nasal provocation with cold, dry air. Am Rev Respir Dis 133:1133–1137PubMedGoogle Scholar
  43. 43.
    Togias A, Proud D, Kagey-Sobotka A, Norman PS, Naclerio RM (1987) The effect of a topical tricyclic antihistamine on the response of the nasal mucosa to challenge with cold, dry air and histamine. J Allergy Clin Immunol 79:599–604PubMedGoogle Scholar
  44. 44.
    Togias A, Lykens K, Kagey-Sobotka A, Eggleston PA, Proud D, Lichtenstein LM, Naclerio RM (1990) Studies on the relationships between sensitivity to cold, dry air, hyperosmolal solutions, and histamine in the adult nose. Am Rev Respir Dis 141:1428–1433PubMedGoogle Scholar
  45. 45.
    Togias AG, Lai G, Philip G (1994) Hyperosmolar nasal challenge stimulates reflex nasal secretion (abstract). J Allergy Clin Immunol 93:217Google Scholar
  46. 46.
    Wagenmann M, Baroody FM, Kagey-Sobotka A, Lichtenstein LM, Naclerio RM (1992) Effect of H1-antagonism (H1-ant) on nasal reflexes after unilateral nasal allergen challenge (abstract). J Allergy Clin Immunol 89:205Google Scholar
  47. 47.
    White MV (1993) Nasal cholinergic hyperresponsiveness in atopic subjects studied out of season. J Allergy Clin Immunol 92:278–287PubMedCrossRefGoogle Scholar
  48. 48.
    Wihl JA, Mygind N (1977) Studies on the antigen-challenged nasal mucosa. Acta Otolaryngol (Stockh) 84:281–293CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • G. Philip
    • 1
  • A. G. Togias
    • 1
  1. 1.Department of Medicine, Division of Allergy and Clinical ImmunologyJohns Hopkins Asthma & Allergy CenterBaltimoreUSA

Personalised recommendations