Rhinitis and Cough

  • Peter K. Smith


A cough is a complex neurogenic reflex that forms part of the innate protective mechanisms of the airways. The function of coughing is to clear the airways of noxious stimuli (microbes, chemicals, and physical); however, many medical conditions, including those of the upper airways, evoke cough, which in itself may be a major symptom of the particular disease state. This chapter is structured to overview the neural and molecular mechanisms involved in the detection and reaction to stimuli, causes of cough with a focus on upper airway etiologies, and two case studies to contextualize this information.


Airways Cough Rhinitis Transient receptor potential vanilloid receptor (TRPV1) Transient receptor potential ankyrin 1 receptor (TRPA1) Gastroesophageal reflux disease (GERD) 


  1. 1.
    Hamizan AW, Christensen JM, Ebenzer J, Oakley G, Tattersall J, Sacks R, et al. Middle turbinate edema as a diagnostic marker of inhalant allergy. Int Forum Allergy Rhinol. 2017;7(1):37–42. Scholar
  2. 2.
    Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, Baroody F, et al. EPOS 2012: European position paper on rhino-sinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. Rhinology. 2012;50(1):1–12. Scholar
  3. 3.
    Mbarek C, Akrout A, Khamassi K, Ben Gamra O, Hariga I, Ben Amor M, et al. Recurrent upper respiratory tract infections in children and allergy. A cross-sectional study of 100 cases. Tunis Med. 2008;86(4):358–61.PubMedGoogle Scholar
  4. 4.
    Ulanovski D, Barenboim E, Raveh E, Grossman A, Azaria B, Shpitzer T. Sinusitis in pilots of different aircraft types: is allergic rhinitis a predisposing factor? Am J Rhinol. 2008;22(2):122–4.CrossRefPubMedGoogle Scholar
  5. 5.
    Southwood JE, Hoekzema CR, Samuels TL, Wells C, Poetker DM, Johnston N, et al. The impact of pepsin on human nasal epithelial cells in vitro: a potential mechanism for extraesophageal reflux induced chronic rhinosinusitis. Ann Otol Rhinol Laryngol. 2015;124(12):957–64. Scholar
  6. 6.
    Pinnock CB, Graham NM, Mylvaganam A, Douglas RM. Relationship between milk intake and mucus production in adult volunteers challenged with rhinovirus-2. Am Rev Respir Dis. 1990;141(2):352–6.CrossRefPubMedGoogle Scholar
  7. 7.
    Rimmer J, Hellgren J, Harvey RJ. Simulated postnasal mucus fails to reproduce the symptoms of postnasal drip in rhinitics but only in healthy subjects. Rhinology. 2015;53(2):129–34.PubMedGoogle Scholar
  8. 8.
    Brusch AM, Clarke RC, Platt PR, Phillips EJ. Exploring the link between pholcodine exposure and neuromuscular blocking agent anaphylaxis. Br J Clin Pharmacol. 2014;78(1):14–23. Scholar
  9. 9.
    Bisgaard H, Study Group on Montelukast and Respiratory Syncytial Virus. A randomized trial of montelukast in respiratory syncytial virus postbronchiolitis. Am J Respir Crit Care Med. 2003;167(3):379–83.CrossRefPubMedGoogle Scholar
  10. 10.
    Wang K, Birring SS, Taylor K, Fry NK, Hay AD, Moore M, et al. Montelukast for postinfectious cough in adults: a double-blind randomised placebo-controlled trial. Lancet Respir Med. 2014;2(1):35–43. Scholar
  11. 11.
    Macpherson LJ, Geierstanger BH, Viswanath V, Bandell M, Eid SR, Hwang S, et al. The pungency of garlic: activation of TRPA1 and TRPV1 in response to allicin. Curr Biol. 2005;15(10):929–34.CrossRefPubMedGoogle Scholar
  12. 12.
    Nilius B, Appendino G. Spices: the savoury and beneficial science of pungency. Rev Physiol Biochem Pharmacol. 2013;164:1–76. Scholar
  13. 13.
    Widdicombe JG. Neurophysiology of the cough reflex. Eur Respir J. 1995;8:1193–202.CrossRefPubMedGoogle Scholar
  14. 14.
    Shannon R, Baekey DM, Morris KF, Nuding SC, Segers LS, Lindsey BG. Production of reflex cough by brainstem respiratory networks. Pulm Pharmacol Ther. 2004;17:369–76.CrossRefPubMedGoogle Scholar
  15. 15.
    Mazzone SB, Cole LJ, Ando A, Egan GF, Farrell MJ. Investigation of the neural control of cough and cough suppression in humans using functional brain imaging. J Neurosci. 2011;31(8):2948–58.CrossRefPubMedGoogle Scholar
  16. 16.
    Mazzone SB. An overview of the sensory receptors regulating cough. Cough. 2005;1:2.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Canning BJ, Reynolds SM, Mazzone SB. Multiple mechanisms of reflex bronchospasm in guinea pigs. J Appl Physiol. 2001;91:2642–53.CrossRefPubMedGoogle Scholar
  18. 18.
    Mario Polverin M, Francesca Polverino F, Marco Fasolino M, Filippo Andò F, Antonio Alfieri A, De Blasio F. Anatomy and neuro-pathophysiology of the cough reflex arc. Multidiscip Respir Med. 2012;7:5.CrossRefGoogle Scholar
  19. 19.
    Mazzone SB, Undem BJ. Cough sensors. V. Pharmacological modulation of cough sensors. Handb Exp Pharmacol. 2009;187:99–127.CrossRefGoogle Scholar
  20. 20.
    Song WJ, Chang YS, Morice AH. Changing the paradigm for cough: does ‘cough hypersensitivity’ aid our understanding? Asia Pac Allergy. 2014;4:3–13.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature. 1997;389:816–24.CrossRefPubMedGoogle Scholar
  22. 22.
    Henrich F, Magerl W, Klein T, Greffrath W, Treede RD. Capsaicin-sensitive C- and A-fibre nociceptors control long-term potentiation-like pain amplification in humans. Brain. 2015;138(Pt 9):2505–20.CrossRefPubMedGoogle Scholar
  23. 23.
    Shim WS, Tak MH, Lee MH, Kim M, Kim M, Koo JY, et al. TRPV1 mediates histamine-induced itching via the activation of phospholipase A2 and 12-lipoxygenase. J Neurosci. 2007;27(9):2331–7.CrossRefPubMedGoogle Scholar
  24. 24.
    Lee LY, Gu Q. Role of TRPV1 in inflammation-induced airway hypersensitivity. Curr Opin Pharmacol. 2009;9(3):243–9.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Nilius B, Owsianik G. The transient receptor potential family of ion channels. Genome Biol. 2011;12:218.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Tominaga M, Caterina MJ, Malmberg AB, Rosen TA, Gilbert H, Skinner K, et al. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron. 1998;21:531–43.CrossRefPubMedGoogle Scholar
  27. 27.
    Bessac BF, Sivula M, von Hehn CA, Escalera J, Cohn L, Jordt SE. TRPA1 is a major oxidant sensor in murine airway sensory neurons. J Clin Invest. 2008;118(5):1899–910.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Bandell M, Story GM, Hwang SW, Viswanath V, Eid SR, Petrus MJ, et al. Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron. 2004;41:849–57.CrossRefPubMedGoogle Scholar
  29. 29.
    Enyedi P, Czirják G. Molecular background of leak K+ currents: two-pore domain potassium channels. Physiol Rev. 2010;90:559–605.CrossRefPubMedGoogle Scholar
  30. 30.
    Sluka KA, Winter OC, Wemmie JA. Acid-sensing ion channels: a new target for pain and CNS diseases. Curr Opin Drug Discov Devel. 2009;12:693–704.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Reznikov LR, Meyerholz DK, Adam RJ, Abou Alaiwa M, Jaffer O, Michalski AS, et al. Acid-sensing ion channel 1a contributes to airway hyperreactivity in mice. PLoS One. 2016;11(11):e0166089. Scholar
  32. 32.
    Hattori M, Gouaux E. Molecular mechanism of ATP binding and ion channel activation in P2X receptors. Nature. 2012;485:207–12.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    G B, Brouns I, Adriaensen D, Timmermans JP. Purinergic signaling in the airways. Pharmacol Rev. 2012;64(4):834–68.CrossRefGoogle Scholar
  34. 34.
    Groneberg DA, Niimi A, Dinh QT, Cosio B, Hew M, Fischer A, Chung KF. Increased expression of transient receptor potential vanilloid-1 in airway nerves of chronic cough. Am J Respir Crit Care Med. 2004;170(12):1276–80.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    O’Connell F, Thomas VE, Pride NB, Fuller RW. Capsaicin cough sensitivity decreases with successful treatment of chronic cough. Am J Respir Crit Care Med. 1994;150:374–80.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Grace MS, Belvisi MG. TRPA1 receptors in cough. Pulm Pharmacol Ther. 2011;24(3):286–8. Scholar
  37. 37.
    El-Hashim AZ, Jaffal SM. Nerve growth factor enhances cough and airway obstruction via TrkA receptor- and TRPV1-dependent mechanisms. Thorax. 2009;64:791–7.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Diogenes A, Akopian AN, Hargreaves KM. NGF up-regulates TRPA1: implications for orofacial pain. J Dent Res. 2007;86:550–5.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Ji RR, Samad TA, Jin SX, Schmoll R, Woolf CJ. p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron. 2002;36:57–68.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Kobayashi H, Gleich GJ, Butterfield JH, Kita H. Human eosinophils produce neurotrophins and secrete nerve growth factor on immunologic stimuli. Blood. 2002;99:2214–20.CrossRefPubMedGoogle Scholar
  41. 41.
    Raap U, Deneka N, Bruder M, Kapp A, Wedi B. Differential upregulation of neurotrophin receptors and functional role of neurotrophins on peripheral blood eosinophils of patients with atopic dermatitis, allergic rhinitis and nonatopic healthy controls. Clin Exp Allergy. 2008;38:1493–8.CrossRefPubMedGoogle Scholar
  42. 42.
    Khan AA, Diogenes A, Jeske NA, Henry MA, Akopian A, Hargreaves KM. Tumor necrosis factor alpha enhances the sensitivity of rat trigeminal neurons to capsaicin. Neuroscience. 2008;155:503–9.CrossRefPubMedGoogle Scholar
  43. 43.
    Alenmyr L, Herrmann A, Högestätt ED, Greiff L, Zygmunt PM. TRPV1 and TRPA1 stimulation induces MUC5B secretion in the human nasal airway in vivo. Clin Physiol Funct Imag. 2011;31(6):435–44. Scholar
  44. 44.
    Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol. 2007;81:1–5.CrossRefPubMedGoogle Scholar
  45. 45.
    Saenz SA, Taylor BC, Artis D. Welcome to the neighborhood: epithelial cell-derived cytokines license innate and adaptive immune responses at mucosal sites. Immunol Rev. 2008;226:172–90. Scholar
  46. 46.
    Wilson SR, Thé L, Batia LM, Beattie K, Katibah GE, McClain SP, et al. The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Cell. 2013;155(2):285–95. Scholar
  47. 47.
    Hensellek S, Brell P, Schaible HG, Brauer R, Segond v BG. The cytokine TNFalpha increases the proportion of DRG neurones expressing the TRPV1 receptor via the TNFR1 receptor and ERK activation. Mol Cell Neurosci. 2007;36:381–91.CrossRefPubMedGoogle Scholar
  48. 48.
    Wessler IA, Kirkpatrick CJ, Rack K. Non-neuronal acetylcholine, a locally acting molecule, widely distributed in biological systems: expression and function in humans. Pharmacol Ther. 1998;77:59–79.CrossRefPubMedGoogle Scholar
  49. 49.
    Remheimer T, Baumgartner D, Oelert H, Racke K, Wessler I. Acetylcholine inhibits ionophore-induced histamine release from human bronchi via stimulation of muscarinic receptors. Naunyn Schmiedebergs Arch Pharmacol. 1996;353(Suppl):R79.Google Scholar
  50. 50.
    Remheimer T, Baumgsrtner D, Hohle K-D, Racke K, Wessler I. Acetylcholine inhibits histamine release from human isolated bronchi via stimulation of muscaric receptors. Am J Respir Crit Care Med. 1997;156:389–95.CrossRefGoogle Scholar
  51. 51.
    Reinheimer T, Münch M, Bittinger F, Racké K, Kirkpatrick CJ, Wessler I. Glucocorticoids mediate reduction of epithelial acetylcholine content in the airways of rats and humans. Eur J Pharmacol. 1998;349:277–84.CrossRefPubMedGoogle Scholar
  52. 52.
    Lee LY, Burki NK, Gerhardstein DC, Gu Q, Kou YR, Xu J. Airway irritation and cough evoked by inhaled cigarette smoke: role of neuronal nicotinic acetylcholine receptors. Pulmonary Pharmacol Ther. 2007;20(4):355–64.CrossRefGoogle Scholar
  53. 53.
    Kichko TI, Lennerz J, Eberhardt M, Babes RM, Neuhuber W, Kobal G, et al. Bimodal concentration-response of nicotine involves the nicotinic acetylcholine receptor, transient receptor potential vanilloid type 1, and transient receptor potential ankyrin 1 channels in mouse trachea and sensory neurons. J Pharmacol Exp Ther. 2013;347(2):529–39. Scholar
  54. 54.
    Hecker A, Mikulski Z, Lips KS, Pfeil U, Zakrzewicz A, Wilker S, et al. Pivotal advance: up-regulation of acetylcholine synthesis and paracrine cholinergic signaling in intravascular transplant leukocytes during rejection of rat renal allografts. J Leukoc Biol. 2009;86(1):13–22. Scholar
  55. 55.
    Skok MV. To channel or not to channel? Functioning of nicotinic acetylcholine receptors in leukocytes. J Leukoc Biol. 2016;86(1):1–3.CrossRefGoogle Scholar
  56. 56.
    Chen C-Y, Joad JP, Bric J, Bonham AC. Central mechanisms I: plasticity of central pathways. Handb Exp Pharmacol. 2009;187:187–201.CrossRefGoogle Scholar
  57. 57.
    Canning BJ. Afferent nerves regulating the cough reflex: mechanisms and mediators of cough in disease. Otolaryngol Clin N Am. 2010;43(1):15–vii. Scholar
  58. 58.
    Ashley Woodcock A, Young EC, Smith JA. New insights in cough. Br Med Bull. 2010;96(1):61–73. Scholar
  59. 59.
    Wong IW, Rees G, Greiff L, Myers JC, Jamieson GG, Wormald PJ. Gastroesophageal reflux disease and chronic sinusitis: in search of an esophageal-nasal reflex. Am J Rhinol Allergy. 2010;24(4):255–9. Scholar
  60. 60.
    Braunstahl GJ, Overbeek SE, Fokkens WJ, Kleinjan A, McEuen AR, Walls AF, et al. Segmental bronchoprovocation in allergic rhinitis patients affects mast cell and basophil numbers in nasal and bronchial mucosa. Am J Respir Crit Care Med. 2001;164(5):858–65.CrossRefPubMedGoogle Scholar
  61. 61.
    Braunstahl GJ, Kleinjan A, Overbeek SE, Prins JB, Hoogsteden HC, Fokkens WJ. Segmental bronchial provocation induces nasal inflammation in allergic rhinitis patients. Am J Respir Crit Care Med. 2000 Jun;161(6):2051–7.CrossRefPubMedGoogle Scholar
  62. 62.
    Braunstahl GJ, Fokkens WJ, Overbeek SE, KleinJan A, Hoogsteden HC, Prins JB. Mucosal and systemic inflammatory changes in allergic rhinitis and asthma: a comparison between upper and lower airways. Clin Exp Allergy. 2003;33(5):579–87.CrossRefPubMedGoogle Scholar
  63. 63.
    Braunstahl GJ, Overbeek SE, Kleinjan A, Prins JB, Hoogsteden HC, Fokkens WJ. Nasal allergen provocation induces adhesion molecule expression and tissue eosinophilia in upper and lower airways. J Allergy Clin Immunol. 2001;107(3):469–76.CrossRefPubMedGoogle Scholar
  64. 64.
    Irwin RS, Baumann MH, Bolser DC, Boulet L-P, Braman SS, Brightling CE, et al. Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines. Chest. 2006;129(1 Suppl):1S–23S.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Schindlbeck NE, Heinrich C, Huber RM, Müller-Lissner SA. Effects of albuterol (salbutamol) on esophageal motility and gastroesophageal reflux in healthy volunteers. JAMA. 1988;260(21):3156–8.CrossRefPubMedGoogle Scholar
  66. 66.
    Rachelefsky GS, Goldberg M, Katz RM, Boris G, Gyepes MT, Shapiro MJ, et al. Sinus disease in children with respiratory allergy. J Allergy Clin Immunol. 1978;61(5):310–4.CrossRefPubMedGoogle Scholar
  67. 67.
    Bjermer L. The nose as an air conditioner for the lower airways. Allergy. 1999;54(Suppl 57):26–30.CrossRefPubMedGoogle Scholar
  68. 68.
    Chong LY, Head K, Hopkins C, Philpott C, Glew S, Scadding G, Burton MJ, et al. Saline irrigation for chronic rhinosinusitis. Cochrane Database Syst Rev. 2016;(4):CD011995.
  69. 69.
    Takahama K, Tetsuya Shirasaki T. Central and peripheral mechanisms of narcotic antitussives: codeine-sensitive and -resistant coughs. Cough. 2007;3:8.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Millqvist E, Ternesten-Hasséus E, Bende M. Inhalation of menthol reduces capsaicin cough sensitivity and influences inspiratory flows in chronic cough. Respir Med. 2013;107(3):433–8. Scholar
  71. 71.
    Galeotti N, Di Cesare Mannelli L, Mazzanti G, Bartolini A, Ghelardini C. Menthol: a natural analgesic compound. Neurosci Lett. 2002;322(3):145–8.CrossRefPubMedGoogle Scholar
  72. 72.
    Karashima Y, Damann N, Prenen J, Talavera K, Segal A, Voets T, Nilius B. Bimodal action of menthol on the transient receptor potential channel TRPA1. J Neurosci. 2007;27(37):9874–84.CrossRefPubMedGoogle Scholar
  73. 73.
    Fokkens W, Peter Hellings P, Segboer C. Capsaicin for rhinitis. Curr Allergy Asthma Rep. 2016;16:60. Scholar
  74. 74.
    Adeleye IA, Opiah L. Antimicrobial activity of extracts of local cough mixtures on upper respiratory tract bacterial pathogens. West Indian Med J. 2003;52(3):188–90.PubMedGoogle Scholar
  75. 75.
    Jeyakumar A, Brickman TM, Haben M. Effectiveness of amitriptyline versus cough suppressants in the treatment of chronic cough resulting from postviral vagal neuropathy. Laryngoscope. 2006;116(12):2108–12.CrossRefPubMedGoogle Scholar
  76. 76.
    Gibson PG, Vertigan AE. Gabapentin in chronic cough. Pulm Pharmacol Ther. 2015;35:145–8. Scholar
  77. 77.
    Ryan NM. Gibson PG recent additions in the treatment of cough. Thoracic Dis. 2014;6(Suppl 7):S739–47.Google Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Peter K. Smith
    • 1
  1. 1.Department of Clinical MedicineGriffith UniversitySouthportAustralia

Personalised recommendations